Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH3:12].N#N.O.NN>CO.[Ni]>[NH2:9][C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([Br:1])=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: [Ni]
Agent: N#N
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(Br)c(C)cc1N
Yield: 86.6 %

Procedure:
316 g of 2-bromo-5-nitro-p-xylene were dissolved in 3000 ml of methanol, freshly produced Raney nickel (about 4 g) was added under a vigorous stream of N2, and the mixture was heated to reflux with vigorous stirring. 275 ml of hydrazine hydrate (80% in water) were then slowly added dropwise. When the dropwise addition was complete (duration about 5 hours), the mixture was refluxed for about a further 6 hours. The catalyst was filtered off, the methanol was removed in a rotary evaporator, the residue was taken up in ethyl acetate, and the solution was washed by shaking with water, dried and re-evaporated in a rotary evaporator. The resultant crude product was recrystallized from heptane, giving 238 g (87%) of pale-green crystals.
Reaction SMILES: [Na].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=O.[CH3:10][C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:12]>>[C:5]1(=[O:7])[O:9][C:2](=[O:8])[CH:3]=[CH:4]1.[CH3:12][C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:10]
Reactant: O=C(O)/C=C\C(=O)O
Agent: C=C(C)CC(C)(C)C
Agent: [Na]
Product: O=C1C=CC(=O)O1

Procedure:
Type B is the sodium salt of a copolymer of maleic acid and 2,4,4-trimethylpent-1-ene obtained by hydrolysis of a copolymer of maleic anhydride and 2,4,4-trimethylpent-1-ene. Latter copolymer is obtainable in accordance with Example 3 of EP-A 9169. Instead of isolating the unhydrolyzed copolymer by spray drying as in Example 3 of EP-A 9169, 325 parts of water are added to the suspension and excess diisobutene is distilled off by steam distillation (bath temperature 80° C.). When an internal temperature of 98° C. is reached, steam is passed in for a further 1 h. Following the addition of a further 220 parts of water and 200 parts of 50% strength by weight sodium hydroxide solution, the mixture is stirred at 1000C until a virtually clear aqueous solution is obtained (about 4 h). The solids content is then adjusted to 25% using water. The pH of the solution is 10. The K value of the copolymer (determined in accordance with Fikentscher as a 1% strength by weight solution in dimethylformamide) is in the range of 30–40.
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[C@@H:3]([N:20]1[C:26](=[O:27])[C@H:25]2[C@@H:21]1[O:22][C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N:24]2)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:35]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:28]1([C:23]2[O:22][C@H:21]3[C@H:25]([C:26](=[O:27])[N:20]3[C@H:3]([C:2]([CH2:1][Cl:35])=[CH2:34])[C:4]([O:6][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:5])[N:24]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCl
Reactant: C=C(C)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21

Procedure:
A solution of 100 mg of Compound (1a) in 3 ml of methylene chloride is mixed with 0.2 ml of a 1.66 N solution of chlorine in carbon tetrachloride at 38° C. with stirring under nitrogen atmosphere to yield Compound (7) after silica gel chromatography.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[OH:1][CH:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)Cc1ccncc1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2'-oxopropyl)-pyridine (13.7 g) in methanol (135 ml), sodium borohydride (3.0 g) was added in portions. After stirring for 2 hours, the mixture was taken to dryness in vacuo. The residue was distributed between ethyl acetate and a minimum of water sufficient to dissolve inorganic salts. The organic phase was dried and evaporated to yield 4-(2'-hydroxypropyl)-pyridine as a colourless oil. The oil was dissolved in acetic acid (100 ml) and hydrogenated in the presence of Adam's catalyst (1 g) until 3 equivalents of hydrogen were consumed. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to yield crude 4-(2'-hydroxypropyl)-piperidine which was used directly in the next step. In analogous manner 4-(2'-hydroxybutyl)-piperidine was prepared from 4-(2'-oxobutyl)-pyridine.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+].[O-2:8].[Mg+2:9].[OH-]>O>[NH3:6].[OH2:2].[OH2:8].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mg+2:9]
Reactant: [NH4+]
Reactant: [O-2]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: N

Procedure:
reacting ammonium sulfate with magnesium oxide or hydroxide at a temperature of not more than 200° C. to form NH3, water and magnesium sulfate heptahydrate or an aqueous solution or slurry containing magnesium sulfate in a concentration of at least 15% by weight; recovering NH3 ;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[CH2:10][N:11]1[CH2:16][C@H:15]([CH3:17])[NH:14][C@H:13]([CH3:18])[CH2:12]1.[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([S:28]([N:14]2[C@@H:13]([CH3:18])[CH2:12][N:11]([CH2:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:19])[CH2:16][C@H:15]2[CH3:17])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]
Reactant: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1

Procedure:
The title compound was prepared from the product of Example 15 step (ii) (0.2 g) and 3-cyanobenzenesulphonyl chloride (0.28 g) by the method of Example 74 as a white solid. Yield 8 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:21]=2)=[CH:14][CH:13]=1>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:29]/[C:25]1[CH:24]=[C:23]2[C:28]([C:20](/[CH:19]=[CH:18]/[C:15]3[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=3)=[N:21][N:22]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccc(Br)cc43)cc21
Yield: 76.5 %

Procedure:
The title compound was prepared from 5-bromooxindole (36 mg, 0.171 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (65 mg, 0.171 mmol) as described in Example A57 part B to give, after silica gel column chromatography (Eluent: 98:2 CH2Cl2/MeOH) the title compound as a yellow oil (75 mg, 77%). MS ESI 573.4 [M+H]+, calcd for [C29H29BrN4O2Si+H]+ 573.13.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].[Br:16]Br.S(=O)(=O)(O)[O-].[Na+]>[Fe](Cl)(Cl)Cl.O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Reactant: BrBr
Agent: Cl[Fe](Cl)Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A three neck flask was charged with 2-nitrobiphenyl (1 mol), iron trichloride (55 mmol), and water (200 mL) and set to stir under a nitrogen atmosphere for 30 minutes. Bromine (1.25 mol) was added dropwise over the course of one hour, then set to reflux for four hours, cooled to 60° C., and stirred for 12 hours. Sodium bisulfate (500 mmol) was added slowly, and the mixture rinsed three times with water (200 mL), twice with 5% sodium hydroxide solution (100 ml) and twice more with water (200 mL). The solids were dissolved in dichloromethane, dried over magnesium sulfate, and flashed chromatographed over silica with dichloromethane as the eluent. The solvent was removed under reduced pressure and the crude product recrystallized from ethanol to give 4′-bromo-2-nitrobiphenyl in 35% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>ClCCl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([N:29]([CH3:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:14]
Reactant: O=C(O)c1nnc2ccccc2c1O
Reactant: CNc1ccccn1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1nnc2ccccc2c1O)c1ccccn1
Reaction time: 1 h
Yield: 14 %

Procedure:
4-Hydroxy-cinnoline-3-carboxylic acid (8.8 g) is dissolved in dichloromethane (600 ml) in the presence of triethylamine (5.6 g). To this solution ethyl chloroformate (6 g) diluted with dichloromethane (50 ml) is added dropwise under stirring at a temperature varying between 0° C. and about 5° C. The mixture is allowed to react at 0°-5° C. for 1 hour, then 2-methylamino-pyridine (4.55 g) is added. The reaction mixture is kept at 0°-5° C. for 1 hour, then at room temperature for 2 hours, under stirring. The organic solution is washed with 2.5% NaHCO3 and water, then is evaporated to dryness in vacuo. The residue is purified over a SiO2 column using ethyl acetate, then ethylacetate-methanol=95:5 as eluents. Crystallization from ethanol yields 1.65 g of 4-hydroxy-N-methyl-N-(2-pyridyl)-cinnoline-3-carboxamide, m.p. 237°-239° C., NMR (DMSO d6) δ ppm: 3.43 (s) (3H, CH3), 7.0-8.3 (m) (8H, phenyl and pyridyl protons).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([N:19]3[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:36])[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][CH:28]=4)[CH2:20]3)[N:13]=[N:14][C:15]=2[C:16]([NH2:18])=[O:17])=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:38][OH:39]>>[C:16]([C:15]1[N:14]=[N:13][C:12]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:36])[C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH3:35])=[CH:31][CH:32]=3)[CH2:20]2)=[N:11][C:10]=1[NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1](=[NH:2])[O:39][CH3:38])=[CH:8][CH:7]=1)(=[O:17])[NH2:18]
Reactant: CCOc1ccc(C(=O)N[C@@H]2CCCN(c3nnc(C(N)=O)c(Nc4ccc(C#N)cc4)n3)C2)cc1
Reactant: CO
Agent: Cl
Product: CCOc1ccc(C(=O)N[C@@H]2CCCN(c3nnc(C(N)=O)c(Nc4ccc(C(=N)OC)cc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-5-(4-Cyanophenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (194) (90 mg, 0.18 mmol) was dissolved in 25 mL dry MeOH. It was chilled in an ice bath, and was then charged with HCl gas from a lecture bottle using a long needle to bubble the gas into the bottom of the solution until saturation reached. The resulting mixture was stirred at RT for overnight, and was placed back to the ice bath for repeated HCl gas charging till saturation. The resulting mixture was stirred for another overnight, and concentrated in vacuo to dryness to afford crude (R)-methyl 4-(6-carbamoyl-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)benzimidate (501). It was dissolved in 15 mL dry MeOH. To it was added dimethylamine (2M in THF, 1.0 mL). The mixture was sent to 60° C. bath and stirred for 1 hour. It was cooled to RT, concentrated in vacuo, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and next MeCN as mobile phases to isolate the title compound, (R)-5-(4-(N,N-dimethylcarbamimidoyl)phenylamino)-3-(3-(4-ethoxybenzamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (502), as HCl salt (59 mg). LC-MS (ESI): m/z (M+1) 532.2. UV: λ=267 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([Cl:27])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: C1CCOC1
Product: Cc1nc2cccc(NC(=O)c3cccc(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 80 °C
Yield: 47.1 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.46 g, 1.5 mmol) in tetrahydrofuran (10 mL), was added 3-chlorobenzoyl chloride (0.68 mL, 5.3 mmol) and heated at 80° C. for three hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-benzamide as a white solid (300 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 7.04 min (98.2%); mp, 326-328° C.; 1HNMR (DMSO-d6)2.18-2.28 (m, 1H, CHH), 2.61-2.92 (m, 6H, CHCH2, CH3), 5.36 (dd, J=6, 11 Hz, 1H, CH), 7.37-8.70 (m, 7H, Ar), 11.12 (s, 1H, NH), 12.72 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.39, 30.66, 40.41, 56.90, 115.69, 121.28, 125.21, 127.12, 131.13, 132.14, 135.78, 163.46, 169.30, 172.59, 172.62. LCMS MH=425, 427; Anal Calcd For C21H17N4O4Cl+0.3H2O: C, 58.62; H, 4.12; N, 13.02; Cl, 8.24. Found: C, 58.46; H, 3.74; N, 12.70; Cl, 7.98.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[F:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[F:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1F)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(F)c2)n1
Reaction time: 1 h

Procedure:
Sodium hydride (60% suspension in oil, 0.48 g, 12.0 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (60 mL). Neat 3-methylpyrazole (0.48 mL, 6.0 mmol) was added. Stirring was continued until the gas evolution subsided. The (2,4-difluoro-phenyl)-(6,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepin-10-yl)-methanone of Step B (2.0 g, 5.9 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 1 hour, cooled and partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with hexane-ethyl acetate (gradient from 9:1 to 1:1) provided the title compound along with the more polar 4-fluoro regioisomer of Example 9. The title compound (0.30 g) was obtained as a foam which crystallized by sonication from hexane-ethanol, m.p. 122-125° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[NH2:16]>CC(O)C>[ClH:1].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[NH:16][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccccc1COc1ccc(N)cc1OC
Reactant: Clc1ncnc2ccsc12
Solvent: CC(C)O
Product: COc1ccccc1COc1ccc(Nc2ncnc3ccsc23)cc1OC
Product: Cl
Yield: 82 %

Procedure:
4-Chlorothieno[3,2-d]pyrimidine (0.102 g, 0.60 mmol) and 3-methoxy-4-(2-methoxybenzyloxy)aniline (prepared according to the published method: WO 96/09294) (0.181 g, 0.70 mmol) were reacted in 2-propanol (3 ml) for 75 minutes according to Procedure A. The product was obtained as off-white prisms (0.211 g, 82%) with m.p. 207-208° C.; (Found: C, 58.55; H, 4.76; N, 9.53. C21H19N3O3S.HCl requires: C, 58.55; H, 4.69; N, 9.77%); δH [2H6]-DMSO 8.85 (1H, s, 2-H), 8.41 (1H, d, J 7, 6 H or 7 H) 7.55 (1H, d, J 7, 6-H or 7-H), 7.42 (1H, d, J 9, 6′-H), 7.34 (1H, t, J 8, 4″-H), 7.29 (1H, s, 2′-H), 7.02-7.20 (3H, m, 5′-H, 3″-H, 6″-H), 6.98 (1H, t, J 8, 5″-H), 5.08 (2H, s, CH2), 3.83 and 3.79 (2x 3H, 2 x s, 2 x OCH3); m/z 393 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[C:11](Cl)(=[O:19])OC1C=CC=CC=1.CO.[NH3:23]>N1C=CC=CC=1>[C:11]([O:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)(=[O:19])[NH2:23]
Reactant: N
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCc1csc2cncn12
Solvent: c1ccncc1
Solvent: CO
Product: NC(=O)OCc1csc2cncn12
Reaction time: 0.67 h
Yield: 62.6 %

Procedure:
To a solution of 0.5 g (3.24 mmol) of the 3-(hydroxymethyl)imidazo[5,1-b]thiazole prepared in Preparation 55 in 5 ml of pyridine was added 0.54 ml (4.22 mmol) of phenyl chlorocarbonate with ice-cooling, and the mixture was stirred at the temperature for 40 minutes and then at room temperature for 2.5 hours. To this solution was added with ice-cooling 20 ml of methanol saturated with ammonia, and the mixture was stirred at the temperature for 30 minutes and then at room temperature for 41 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography using Sephadex LH 20, eluting with a 1:1 mixture of chloroform and methanol to give 0.4 g (yield 62.6%) of the title compound as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N[C:11](=[O:13])[O-:12])C.[CH2:14](O)[CH3:15]>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2]>[CH2:14]([O:12][C:11](=[O:13])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: CCNC(=O)[O-]
Reactant: Nc1ccccc1
Reactant: CCO
Agent: CCCCCCCC(=O)[O-]
Agent: [Zn+2]
Product: CCOC(=O)Nc1ccccc1
Reaction time: 6.5 h

Procedure:
1024 g aniline, 980 g ethylcarbamate, 1060 g ethanol (approximately 96%) and 6.0 g zinc octoate were reacted in the apparatus described in Example 1 for 6.5 hours at 200° C. When the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography (HPLC). A yield of 1580 g (87% of the theoretical yield) of N-phenyl-carbamic acid-ethyl ester was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([Cl:12])=[O:11])=[N:2]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27]/[CH:28]=[CH:29]\[CH2:30][NH2:31])[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl.O.C(=O)([O-])[O-].[Na+].[Na+]>[ClH:12].[ClH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:27]/[CH:28]=[CH:29]\[CH2:30][NH:31][C:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)=[O:11])[CH2:25][CH2:26]1
Reactant: COc1ccccc1N1CCN(C/C=C\CN)CC1
Reactant: O=C(Cl)c1nsc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1N1CCN(C/C=C\CNC(=O)c2nsc3ccccc23)CC1
Product: Cl
Reaction time: 8 h
Yield: 104.1 %

Procedure:
A mixture of 1,2-benzisothiazole-3-carboxylic acid chloride (1.77 g) and Z-1-(2-methoxyphenyl)-4-(4-amino-2-butenyl)piperazine (2.34 g) in dichloromethane (100 ml) was stirred while triethylamine (2.51 ml) was added dropwise. Stirring was continued overnight. After 24 hr, the reaction mixture was diluted with water and saturated aqueous sodium carbonate solution and extracted with dichloromethane. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was taken up in dichloromethane/ether and hydrogen chloride in ether was added. The precipitate was recrystallized from methanol/dichloromethane/ether to provide 2.31 g (51.7%) of product, mp 184-187.
Reaction SMILES: Br[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=2[Cl:19])=[CH:5][CH:4]=1.[OH:22][C:23]1[CH:27]=[C:26]([C:28]2[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=2)[O:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)CC>O.C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:22][C:23]1[CH:27]=[C:26]([C:28]2[CH:33]=[C:32]([CH:31]=[CH:30][CH:29]=2)[CH2:2][C:3]2[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]3[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=3[Cl:19])=[CH:5][CH:4]=2)[O:25][N:24]=1
Reactant: CC(=O)c1ccc(OCc2ccc(CBr)cc2)c(Cl)c1O
Reactant: OB(O)c1cccc(-c2cc(O)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCCO
Product: CC(=O)c1ccc(OCc2ccc(Cc3cccc(-c4cc(O)no4)c3)cc2)c(Cl)c1O
Temperature: 70 °C
Yield: 5.5 %

Procedure:
Add 1-(4-(4-(bromomethyl)benzyloxy)-3-chloro-2-hydroxyphenyl)ethanone (180 mg, 0.487 mmol) and 3-(3-hydroxyisoxazol-5-yl)phenylboronic acid (218 mg, 1.06 mmol) to a 2.0 M solution of Na2CO3 in water (2.36 mL), dimethoxyethane (4.72 mL), and n-PrOH (4.72 mL). Degas the solution. Add tetrakis(triphenylphosphine)palladium (0) (123 mg, 0.106 mmol) and degas the mixture. Heat the mixture at 70° C. for 12 h. Quench the reaction with water. Extract with EtOAc. Dry, filter and concentrate. Purify the residue by flash chromatography on silica gel afforded the title compound (12 mg, 5%): 1H NMR (d6-DMSO) δ 2.61 (s, 3H), 4.02 (s, 2H), 5.31 (s, 2H), 6.51 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 7.31-7.36 (m, 3H), 7.39-7.44 (m, 3H), 7.62 (d, J=7.8 Hz, 1H), 7.70 (s, 1H), 7.93 (d, J=9.4 Hz, 1H), 11.34 (s, 1H), 13.13 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 448 (M−H, 100%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:41]([NH:40][CH3:39])=[O:42])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 88 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 15 mg of methyl isocyanate. After 1.5 h in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 25 mg of title compound. Mass spec (NH3 /CI): 475 (M+1).