Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)[CH:10]=1.[H-].[Na+].Cl[C:27]1[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=1>C1COCC1.O>[C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:10]=2)[CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCN(c2cc(N)ncn2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1
Temperature: 25 °C

Procedure:
1-[4-(6-Amino-pyrimidin-4-yl)-piperazin-1-yl]-ethanone TFA salt (72 mg, 0.22 mmol) was stirred in anhydrous THF under N2. Sodium hydride (26 mg, 60% dispersion, 0.65 mmol) was added followed by the addition of 2-chlorothiazole-5-carbonitrile (62 mg, 0.43 mmol). The reaction was heated to reflux and after 30 minutes additional 2-chloro-thiazole-5-carbonitrile (85 mg, 0.59 mmol) was added. After a total of 1.5 hours, the reaction was cooled to room temperature, diluted with water and the bulk of the tHF was removed in vacuo. The resulting mixture was adjusted to pH 7 with 1 M HCl (aq). The resulting precipitate was filtered, washed with water and after air drying was washed with hexane. 1H-NMR (400 MHz, DMSO) 12.11 (1H, s), 8.45 (1H, s), 8.26 (1H, s), 6.23 (1H, s), 3.62–3.55 (m, 8H), 2.05 (s, 3H). M+1=330.2.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=1>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][C:7]2[CH:8]=[CH:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:11][CH:6]=2)=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: FC(F)(F)Oc1cccc(Br)c1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2cccc(OC(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 1-bromo-3-trifluoromethoxy-benzene. MS m/z 493 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[F:27][CH2:28][CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[F:27][CH2:28][CH2:29][N:30]1[CH:34]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:32]=[N:31]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CCF)c2)OC1(C)C
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: O
Solvent: CO
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(CCF)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (2.1 mg). LCMS (M+H)+: m/z=451.2.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[CH:17]=[C:16]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1[CH2:50][CH2:49]OCC1>>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([N:28]3[CH2:29][CH2:30][N:31]([C:34]4[C:39]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:19]=2)[CH:25]=[CH:24][C:23]=1[F:26].[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([N:28]3[CH2:29][CH2:30][N:31]([C:34]4[C:39]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([CH2:6][CH2:49][CH3:50])[CH2:13][CH2:12]3)[N:19]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)CC1
Reactant: C1COCCO1
Agent: Cl
Product: CCCN1CCC(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)CC1
Product: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(C3CCNCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (97 mg, 0.157 mmol) in dioxane, add 0.5 mL of HCl in dioxane (4M) and stir at room temperature for 2 hours. Concentrate the solution under reduced pressure and wash the residue with dry ether. Discard the ether wash, add additional ether and stir for one hour to give a pale yellow suspension. Collect the solid to afford 4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as the HCl salt. Prepare the freebase by partitioning between EtOAc and 10% NaOH solution. Dry (Na2SO4) and evaporate the EtOAc layer. Dissolve the free base in dichloroethane and add propionaldehyde (0.09 mmol) and sodium triacetoxyborohydride (22 mg, 010 mmol) followed by one drop of HOAc. Stir the mixture for one hour, dilute with DCM and wash with 10% NaOH (1×). Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Chromatograph the residue on a 2 mm preparative TLC plate (5% MeOH(1 N NH3)/DCM eluent) to give 4-(3-chloro-4-fluoro-phenyl)-2-(1-propyl-piperidin-4-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine. 1H NMR (CDCl3): δ 0.93 (t, 3H), 1.59 (m, 2H), 2.05 (m, 6H), 2.37 (m, 2H), 2.75 (m, 1H), 3.08)m, 2H), 3.40 (m, 4H), 3.88 (m, 4H), 6.69 (s, 1H), 7.06 (m, 1H), 7.21 (t, 1H), 7.86-7.93 (m, 2H), 8.08 (d, 1H), 8.47 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@H:7]([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@H:7]([CH3:11])[C:8]([Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](Oc1ccc(O)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: C[C@@H](Oc1ccc(O)cc1)C(=O)Cl

Procedure:
4.0 g (0.022 mol) of (R)-2-(4-hydroxyphenoxy)propionic acid was dissolved in 25 ml of thionyl chloride, the mixture was refluxed for 5 hours, and distilled under a reduced pressure. 3.3 g (0.016 mol) of (R)-2-(4-hydroxyphenoxy)propionic acid chloride thus obtained was dissolved in 60 ml of tetrahydrofuran, and the mixture was cooled to 0° C. 3.04 g (0.018 mol) of 2-amino-5-chlorobenzoxazole and triethylamine dissolved in 15 ml of tetrahydrofuran were sequentially added to the reaction mixture. The mixture was stirred at room temperature for 5 hours, and the solvent was removed therefrom under a reduced pressure. After adding water thereto, the mixture was extracted three times with ethyl acetate three times. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (4.04 g, 75.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>O1CCOCC1.CO>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ccc(-c2ccncc2)cc1
Reaction time: 120 h

Procedure:
Under inert gas atmosphere 181 mg (0.248 mmol) PdCl2(dppf)xCH2Cl2 are added to a mixture of 30.0 g (124 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (1.1), 139 mL (279 mmol) 2N sodium carbonate solution and 16.8 g (136 mmol) pyridine-4-boronic acid in 300 mL 1,4-dioxane and 100 mL methanol. The mixture is stirred for 5 d at reflux. After that time, the residue is poured into water (3 L) and extracted with dichloromethane (3×). The combined organic layers are washed with water and dried over magnesium sulphate. The solvent is evaporated and the residue is triturated with acetone and tert-butyl methyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O.CN(C)C=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1ccc(I)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1Cl
Yield: 74 %

Procedure:
A suspension of 66 g of 2-chloro-4-iodo-benzoic acid (I.G.Farbenind. D.R.P. 565411 1930) in 690 ml of benzene is treated at 4° C. with 20.56 ml of thionyl chloride and 0.1 ml of dimethylformamide and the mixture is boiled at reflux under argon for 21 hrs. The reaction mixture is concentrated. Distillation of the residue at 160°/60 Pa yields 51.9 g (74%) of 2-chloro-4-iodo-benzoyl chloride as a colourless liquid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]([OH:18])[CH2:16]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CCC>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:18][CH:15]([C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[Cl:12])[CH2:16][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCC(O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3Cl)O2)cc1

Procedure:
A mixture of 11.5 parts of 2-bromo-p-chloroacetophenone, 10.4 parts of o-chloro-α-(hydroxymethyl)benzylalcohol, 0.2 parts of p-toluenesulfonic acid, 180 parts of benzene and 80 parts of butanol is stirred and refluxed overnight with water-separator. The solvent is removed in vacuo and the residue is dissolved in chloroform. The chloroform solution is stirred with silica gel for 30 minutes. The silica gel is filtered off and the solvent is removed in vacuo, yielding 2-(bromomethyl)-4-(o-chlorophenyl)-2-(p-chlorophenyl)-1,3-dioxolane as a residue.
Reaction SMILES: [OH:1][C@@H:2]([C:23]([CH3:29])([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:30]([O:1][C@@H:2]([C:23]([CH3:28])([CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)OC(=O)c1ccccc1

Procedure:
In analogy to Example 1(a), 1.6 g of (1S,5R,6R,7R)-6-[(E)-(3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one, 8 ml of pyridine, and 1 ml of benzoyl chloride yield 2 g of the dibenzoate as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10](Cl)=[O:11].[C:14]([CH:16]([OH:30])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)#[N:15].N1C=CC=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10]([O:30][CH:16]([C:14]#[N:15])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:18]=1)=[O:11]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 10.0 g of cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarbonyl chloride in 80 ml of dry benzene, there were added first 8.5 g of α-cyano-3-phenoxybenzyl alcohol and then gradually 4.5 g of pyridine. The mixture was stirred at room temperature overnight. About 70 ml of water was added to the reaction mixture, the benzene layer was separated, washed with water and dried over anhydrous magnesium sulfate, and low-boiling fractions were distilled off under reduced pressure. The oily product thus obtained was purified by preparative liquid chromatography following the procedure of SYNTHESIS EXAMPLE 1 to give 12.1 g (70% yield) of α-cyano-3-phenoxybenzyl cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate with a ratio of racemic modifications D1 /D2 of about 50/50.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[O:10]=[P:11]12[O:22]P3(OP(OP(O3)([O:18]1)=O)(=O)[O:12]2)=O>>[C:2]1([NH2:3])[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH2:9])[N:1]=1.[OH:12][P:11]([OH:22])([OH:18])=[O:10]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: Nc1nc(N)nc(N)n1
Product: O=P(O)(O)O
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
3780 g melamine (30 mol.) are mixed with 2130 g (15 mol.) phosphorus pentoxide in a laboratory ploughshare mixer with an effective volume of 10 l and thermal oil-heated double jacket and heated to a temperature of 200° C. Within 30 min, 630 g (5 mol.) oxalic dihydrate are then added. After a secondary reaction time of a further 15 min, the melamine polyphosphate formed was removed from the mixer.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH:13]=[O:14]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH:13]=[O:14])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9]
Reactant: CNCC=O
Reactant: Cc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: Cc1nnc(NC(=O)N(C)CC=O)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-ureido]acetaldehyde.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.N([O-])=O.[Na+].[CH:16](=[O:22])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>O.C(#N)C>[CH3:2][CH:1]([C:4]1[CH:10]=[CH:9][C:7]([C:20]2[O:21][C:17]([CH:16]=[O:22])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=Cc1ccco1
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1ccc(-c2ccc(C=O)o2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
& B. A mixture of 100 g (0.74 mole) of 4-isopropylaniline (Aldrich Chemical Co.), 100 ml of water, and 200 ml of concentrated hydrochloric acid, was cooled at 5° C. and treated dropwise with a solution of 52 g (0.75 mole) of sodium nitrite in 150 ml of water. The mixture was kept at 5° C. for 1 hour. A solution of 90 g (0.94 mole) of furfural in 150 ml of acetonitrile was added all at once followed by a solution of 30 g of CuCl2.×H2O in 125 ml of water. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was warmed at 45° C. for 30 minutes and then cooled, and extracted with ether (3×400 ml). The combined ethereal extracts were washed with water (3×200 ml), saturated NaHCO3 solution (2×200 ml) and water (2×200 ml). The ethereal extract was dried over MgSOr and the solvent removed in vacuo (water pump). The residual oil was distilled under high vacuum using a flame. The product, 5-[4-(1-methylethyl)phenyl]-2-furancarboxaldehyde (B), was obtained as an oil (26 g, 16% yield); b.p. 160-175° C./0.5 mm Hg.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].C(O)C.O.C([O-])(O)=O.[Na+:31]>O1CCOCC1.[Pd]>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:31]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(O)C1C(=O)N2C(C(=O)[O-])C(=O)CC12
Reaction time: 1 h

Procedure:
Benzyl 6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (30 mg) is dissolved in dioxane (2 ml). The solution is treated with ethanol (0.5 ml), H2O (0.5 ml), NaHCO3 (8.5 mg) and 10% Pd/C (20 mg) and the resulting mixture is hydrogenated at 40 psi for 1 hr. The mixture is filtered to remove the catalyst which is washed with H2O (2.5 ml). The combined filtrate is extracted with ethyl acetate (3×2 ml), concentrated in vacuo, and lyophilized to provide sodium 6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[O:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=3)[CH:3]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cc(Nc3cccc(N)n3)ncn2)cc1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
To a solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (200 mg, 0.90 mmol) in dry DMF (2 mL) was added 4-methoxyphenol (168 mg, 1.3 mmol) and anhydrous K2CO3 (179 mg, 1.3 mmol). The reaction mixture was heated at 100° C. for 16 h under N2 atmosphere. It was then cooled and DMF removed under reduced pressure to give a yellowish gummy residue that was taken in EtOAc (10 mL). The solution was washed with water (5 mL) and brine (5 mL), was dried over Na2SO4 and was then concentrated under reduced pressure to get crude product. This was further purified by column chromatography (SiO2, 60-120, hexane/EtOAc, 5/5) to give N2-(6-(4-methoxylphenoxy)pyrimidin-4-yl)pyridine-2,6-diamine (160 mg, 59.2%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29](I)=[CH:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]3=[N:25][CH:26]=2)[CH:16]=N[C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][N:49]([CH2:51][C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)[CH:50]=2)O1.[C:59](=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29]([C:46]4[CH:47]=[N:48][N:49]([CH2:51][C:52]5[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=5)[CH:50]=4)=[CH:28][N:27]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:59][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ncc(-c2cnc3c(c2)c(I)cn3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: CC1(C)OB(c2cnn(Cc3cccnc3)c2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccnc4)c2)cn3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Yield: 38.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 5-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-6-methoxypyridin-3-yl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 66P) (150 mg, 0.233 mmol) was coupled with 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (intermediate 64) (73 mg, 0.256 mmol) using Pd(PPh3)2Cl2 (9 mg, 0.0116 mol) and sodium carbonate (74 mg, 0.699 mmol) in toluene/ethanol/water (3/3/2 ml) to afford 60 mg (38% yield) of the titled compound after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent. MS: m/z=675.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O:17]=[C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:19]=[CH2:20].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:20][CH2:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)N1CCOCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC(=O)N2CCOCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following the procedure of Example 4, 2,6-bis-(1,1-dimethylethyl)4-mercaptophenol (2.38 g, 0.01 mole) and (1-oxo-2-propenyl)morpholine(1.41 g, 0.01 mole) in methanol (75 ml) were combined with triethylamine (1.5 ml) and stirred for 12 hours at room temperature. The solvent was evaporated under a nitrogen stream leaving an orange oil which was chromatographed over silica. The product was recrystallized from a mixture of hexane, ethyl ether and methanol and the resu-ting white solid dried to yield the title compound, m.p. about 136.5°-137.5° C.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:12]([OH:32])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=[CH:11][C:4]=2[O:3]1.Cl>O.CO>[OH:7][CH2:6][C:5]1[CH:8]=[C:9]([CH:12]([OH:32])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=[CH:11][C:4]=1[OH:3]
Reactant: CC1(C)OCc2cc(C(O)CNCCCCCCOCCCCc3ccccc3)ccc2O1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCc1cc(C(O)CNCCCCCCOCCCCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
To a solution of 0.6 g (1.32 mmol) [2-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-2-hydroxyethyl]-6-[4-phenylbutoxy)hexylamine in 20 ml of a 1:1 H2O/MeOH mixture is added 0.15 ml (1.75 mmol) 35% HCl. After allowing the reaction to stir for 48 hr at room temperature, the MeOH is evaporated off at reduced pressure. The resulting aqueous mixture is extracted with 20 ml CH2Cl2. The organic phase is washed sequentially with 20 ml of a saturated NaHCO3 solution and further 20 ml H2O, dried on anhydrous Na2SO4 and evaporated to dryness to yield 0.24 g (43.9%) 2-hydroxymethyl-4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}phenol.