Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:22][CH:21]([CH3:23])[C:12]2=[C:13](O)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH:21]([CH3:23])[C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:27][CH2:26][CH2:25]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2nc3ccnn3c(O)c21
Reactant: C1CNC1
Product: CC1CNCCc2nc3ccnn3c(N3CCC3)c21

Procedure:
The product was prepared using 10-hydroxy-9-methyl-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (from step c to f), in step e (route 1) azetidine was used as the amine.
Reaction SMILES: C1(N2C=NC3C2=NC(OCC)=NC=3N)CCCC=C1.[CH:20]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[N:30][C:31]=3[NH2:35])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>>[CH2:37]([O:36][C:29]1[N:28]=[C:27]2[C:32]([N:33]=[CH:34][N:26]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:31]([NH2:35])[N:30]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Product: CCCCOc1nc(N)c2ncn(C3CCCCC3)c2n1
Yield: 47 %

Procedure:
The procedure of Example 8 was repeated except that the 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine used therein was replaced by an equivalent weight of 9-(2-cyclohexenyl)-2-n-butoxy-9H-adenine. There was produced the title product in 47% yield; m.p. 138°-141° C. IR(KBr): 3300, 2930, 1660, 1640, 1590, 1405, 1345 cm-1. UV: λmaxEtOH 253 nm(ε7600), 269 nm(ε11500). NMR(CDCl3): 1.50(17H, m), 4.30(1H, m), 4.31(2H, t, J=6 Hz), 6.40(2H, s), 7.67(1H, s).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]#[N:19])[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C#N)c2)cn1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (49 mg, 30%) which was obtained as a white solid. MS (ESI): m/e=327.0 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])(=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.N(Cl)Cl.[NH:21]=[N+:22]=[N-:23]>C1C=CC=CC=1>[CH3:2][C:1]1[N:4]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:23]=[N:22][N:21]=1
Reactant: [N-]=[N+]=N
Reactant: COC(=O)CCCNC(C)=O
Agent: ClNCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)CCCn1nnnc1C
Reaction time: 8 h

Procedure:
Methyl 4-acetamidobutyrate (8 g) is dissolved in benzene (80 ml). Phosphorus pentachloride (12 g, 0.055 mol) is added to the solution with stirring and ice-cooling. The mixture is stirring at room temperature for 1.5 hours and then concentrated to about 1/3 volume under reduced pressure. To the resulting iminochloride solution is added dropwise a solution of hydrogen azide in benzene (0.0173 mol/10 ml, 57.8 ml) with stirring and ice-cooling. The mixture is stirred at room temperature for 1 hour, allowed to stand for overnight and gently refluxed for 2 hours. The reaction mixture is concentrated and ice-water is added to the mixture. The mixture is extracted with chloroform. The chloroform solution is washed with water, dil. aqueous sodium hydroxide and then water and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Wakogel C-200). The column is eluted with chloroform-methanol (50:1) to obtain methyl 4-(5-methyl-1,2,3,4-tetrazol-1-yl)butyrate (5.7 g) as colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 103 starting from 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (preparation analogous to US 2005/176722) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[C@@H:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([C@@H:18]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:19][CH2:20][N:21]([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:23])[CH3:24])[CH:11]=1)(=[O:46])=[O:45]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCO)ccc1OCc1ccccc1)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOS(C)(=O)=O)ccc1OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethanol (Prepared according to WO1998/43942, 1.0 g, 2.25 mmol) was dissolved in dichloromethane (20 ml) and N,N-diisopropyl ethylamine (1.8 ml, 10 mmol) added. The solution was then cooled to 0° C. and methanesulphonyl chloride (0.42 ml, 5.4 mmol) was added. After stirring for 2 hours at 0° C. the mixture was diluted with dichloromethane (20 ml) and washed with water (50 ml), brine (50 ml) and then dried (magnesium sulphate) and the solvent removed in vacuo to yield the title compound as a yellow oil, 1.56 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:13])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cncc(Br)c1

Procedure:
To 5.00 g of 5-bromonicotinic acid, 74 ml of thionyl chloride was added and the mixture was heated at reflux for 6 hours. After the solvent was distilled off under reduced pressure, the crystal was washed with diisopropyl ether and collected by filtration to obtain 4.09 g of the objective compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31](=O)[CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:31][CH3:32])[C:16]2[C:17]([CH3:30])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][OH:29])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC=O
Reactant: COC(=O)c1cc(OCCO)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(OCCO)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a stirred solution of methyl 3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(2-hydroxyethoxy)-2-methylbenzoate (2.0 g, 4.7 mmol) and acetaldehyde (0.63 g, 14.2 mmol) in dichloroethane (20 mL) was added acetic acid (1.7 g, 28 mmol) and the reaction mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (3.0 g, 14.2 mmol) was added at 0° C. and reaction was stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase was separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure; Crude material was purified by column chromatography to afford the title compound (1.9 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:31][CH:28]3[CH2:30][CH2:29]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: NCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCC3CC3)nc3cc(Cl)ccc23)CC1
Yield: 31.8 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.56 mmol), and cyclopropylmethylamine (360 μL, 4.0 mmol) are treated according to method E yielding 53 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(cyclopropylmethylamino)quinoline. 47 mg thereof are treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (19 μL) and triethylamine (140 μL).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[C:6]([O:12][CH3:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1>>[Br:4][C:5]1[C:6]([O:12][CH3:13])=[N:7][C:8]([N:2]([CH3:3])[CH3:1])=[N:9][CH:10]=1
Reactant: CNC
Reactant: COc1nc(Cl)ncc1Br
Product: COc1nc(N(C)C)ncc1Br
Temperature: 45 °C
Yield: 98.2 %

Procedure:
A solution of dimethylamine (2.0 M solution in THF, 17.2 mL, 34.5 mmol) was added to 5-bromo-2-chloro-4-methoxypyrimidine (1.540 g, 6.89 mmol) at RT. The reaction was heated to 45° C. for 30 min, then cooled and concentrated. The residue was washed and filtered with diethyl ether to give 1.57 g of 5-bromo-4-methoxy-N,N-dimethylpyrimidin-2-amine as a light yellow solid. ES+=232.0 (M+H)
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[C:23]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]([CH2:16][CH2:17][CH:18]2[C:27]3[C:22](=[C:23]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)COc1cccc2c1CCCC2CCCO
Reactant: c1ccc(Nc2ccccc2)cc1
Product: COC(=O)COc1cccc2c1CCCC2CCC(=O)N(c1ccccc1)c1ccccc1

Procedure:
By the same procedure as reference example 1→reference example 2→example 1 (using diphenylamine instead of dibenzylamine), using methyl [1-(3-hydroxypropyl)-1,2,3,4-tetrahydronaphthalen-5-yl]oxyacetate instead of methyl(1-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-5-yl)oxyacetate, was obtained methyl [1-(2-diphenylaminocarbonylethyl)-1,2,3,4-tetrahydronaphthalen-5-yl]oxyacetate. By the same procedure as example 2, using methyl [1-(2-diphenylaminocarbonylethyl)-1,2,3,4-tetrahydronaphtahalen-5-yl]oxyacetate thus obtained, the title compound having the following physical data was given.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Cl:7][S:8](O)(=[O:10])=[O:9]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:8]([Cl:7])(=[O:10])=[O:9]
Reactant: Cc1ccsc1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccsc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
A 49-g (0.5 mol) sample of 3-methylthiophene was added in small portions to a cooled solution (-20° C) of 128 g (1 mol) chlorosulfonic acid in 250 cc chloroform. After the addition was completed, the reaction mixture was allowed to warm to about 25° C and then heated at reflux for 30 minutes. The reaction mixture was then diluted with ice water and neutralized with aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to give 30 g of 3-methyl-2-thienylsulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[N:11]=1.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:11]=1
Reactant: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCCc1nc(-c2ccccc2N)co1

Procedure:
Combine 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester (3.0 g, 10.3 mmol) with Pd/C (5%, 450 mg) and Pd/black (50 mg) in THF (150 mL) and react with hydrogen (init. 40 psi) in a Parr® apparatus. When reduction is complete, filter the mixture through Celite® and concentrate the filtrate. Drying allows for recovery of crude 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid methyl ester (2.36 g, 88%). MS (ES): (M+1)+ 261.2 m/z.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>[Cu].CS(C)=O>[F:16][C:10]([F:17])([C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Fc1cnc(Br)nc1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ncc(F)cn1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
To 2-bromo-5-fluoropyrimidine (500 mg, 2.8 mmol) were added DMSO (1.5 mL), ethyl 2-bromo-2,2-difluoroacetate (0.4 mL, 3.1 mmol), and copper powder (390 mg, 6.16 mmol). The reaction vessel was sealed, and then evacuated and flushed with argon (2×). The mixture was heated at 50° C. overnight, then diluted with EtOH and filtered through Celite washing with EtOAc. To the filtrate was added water and the mixture was filtered through Celite again. The separated organic layer was washed with brine (2×), dried over sodium sulfate, and concentrated to afford ethyl 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate as an oil (470 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 2H), 4.41 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH2:38])[C:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[CH3:24][O:25][C:26](=[O:39])[C@@H:27]([NH:38][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:11])=[O:12])[C:28]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)([CH3:30])[CH3:29]
Reactant: COC(=O)[C@@H](N)C(C)(C)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Product: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(C)(C)c1ccc(Cl)cc1
Yield: 90 %

Procedure:
The title compound (61 mg, 90%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (EXAMPLE 101, Part D) and (S)-2-amino-3-(4-chloro-phenyl)-3-methyl-butyric acid methyl ester (EXAMPLE 107, Part F) as in Example 94, Part A. 1H NMR (500 MHz, CDCl3): 11.26 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.21 (dd, J=8.8, 1.0, 1H), 8.07 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.35-7.25 (m, 5H), 6.89 (d, J=8.3, 1H), 6.32 (br d, J=9.2, 1H), 4.97 (d, J=9.0, 1H), 3.64 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1>>[CH:18]1([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[N:3][C:2]([C:35]5[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]6[C:36]=5[CH:37]=[CH:38][NH:39]6)=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)[CH2:20][CH2:19]1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CC4)CC3)cc2n1
Reactant: CC1(C)OB(c2cc(C#N)cc3[nH]ccc23)OC1(C)C
Product: N#Cc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C5CC5)CC4)cc3n2)c2cc[nH]c2c1
Yield: 21.7 %

Procedure:
A mixture of 2-chloro-6-(4-cyclopropyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-H-indole-6-carbonitrile (273 mg) were reacted using Suzuki coupling method B, to give the title compound (55 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[CH2:24]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([F:30])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH2:12]3)[CH:23]=2)[C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20]1)[CH3:25]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1ccc(C2CNCCN2)s1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(C)s4)C3)cc21
Yield: 17.5 %

Procedure:
A mixture of 4.368 g of 2-(5-methyl-2-thienyl)piperazine and 2.152 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 15 ml of pyridine was heated at reflux under argon for 18 hours, then allowed to cool and the solvent removed. The residue was triturated with methanol and ether, then filtered and dried, giving 580 mg of the desired product, mp 200°-210° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:20]#[C:21][NH2:22].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH:21]([NH2:22])[NH:20][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7]1
Reactant: COc1ccccc1CNNC(=O)c1ccccc1
Reactant: N#CN
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1CN1N=C(c2ccccc2)NC1N
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Benzoic acid N′-(2-methoxybenzyl)hydrazide (200 mg, 0.78 mmol from 5.2) was dissolved in a mixture of 1.5 mL dioxane and 1 mL water, combined with 164 mg (3.9 mmol) cyanamide dissolved in 1 mL water, adjusted to pH 2 with 1 N HCl, then stirred for 4 hr at 120° C. in a microwave oven at 200 watts power. The pH was checked every 30 minutes and readjusted to pH 2 as necessary. The resulting solid was then suctioned off, washed with a small quantity of diethyl ether, and dried (65 mg target product in the form of a light yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[OH-].[Na+].[CH3:12]I>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)ccc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
2-Chloro-5-methylphenol (50 mmol, 7.13 g), NaOH pellets (60 mmol, 2.4 g), and methanol (50 ml) were stirred together until a homogeneous solution was obtained. The flask was cooled to 0° C., and methyl iodide (60 mmol, 3.77 ml) was added. The reaction was warmed over 2 hours to ambient and stirred for 16 hours. Reaction was still incomplete by thin layer chromatography; additional NaOH (˜300 mg) and CH3I (˜5 ml) was introduced, and stirring continued for another 24 hours. TLC again indicated incomplete conversion, so additional time and reagents were again applied. The mixture was at length concentrated, diluted with water (50 ml), and extracted with methylene chloride (2×25 ml). The combined organic layer was dried (MgSO4), filtered through silica, and concentrated to afford the title compound as an oil (5.09 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[C:6]=2[CH:15]=1.[H][H]>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:15]=1
Reactant: [H][H]
Reactant: O=C(O)c1cc(=O)c2cc(F)ccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2cc(F)ccc2O1
Yield: 83.3 %

Procedure:
A mixture of 63.4 parts of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid and 400 parts of acetic acid was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in petroleum ether. The product was filtered off and dried in vacuo at about 70° C., yielding 49 parts (83.3%) of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (intermediate 5).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[N:6]1([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:14][CH2:13][CH2:12][CH2:11][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NCCCN1CCCC1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)NCCCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of 27.7 gm (0.39 mole) ethyl isocyanate in 250 mL chloroform were added 50 gm (0.39 mole) 3-(1-pyrrolidinyl)propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and the reaction mixture stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 74.5 gm (96.4%) of the desired urea as a clear oil.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[O:25][CH3:26])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: COc1ccc(C2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2CCOCC2)cc1NC(N)=S
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a stirred solution of 3.25 g (8.77 mmol) 1-benzoyl-3-[2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea in 45 ml methanol was added dropwise 0.25 ml (1.32 mmol) 5.3 M sodium methylate solution and stirring continued for 1 h at room temperature. The mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 1.90 g (81%) [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea as a white foam. ES-MS m/e (%): 267 (M+H+, 100).