Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.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.[Pd].O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(F)cc2)c1
Temperature: 90 °C

Procedure:
A mixture of dimethyl 5-bromoisophthalate (5.47 g, 20.03 mmol), 4-fluorophenylboronic acid (4.20 g, 30.0 mmol) and cesium carbonate (9 g, 27.6 mmol) in dioxane (60 mL) was purged with Ar gas for a few minutes, to the mixture was added Pd(PPh3)4 (1 g, 0.865 mmol). The reaction mixture was heated at 90° C. overnight. The next morning additional Pd-catalyst (˜300 mg) was added, and the reaction mixture was heated at 90° C. for an additional 7 h. To the reaction mixture was added EtOAc and water, and the insoluble material was filtered. The EtOAc layer was separated, dried over MgSO4, concentrated in vacuo and the residual solid was mixed with ether. The insoluble solid was filtered and the filtrate was concentrated. To the residue was added ether, the insoluble solid was filtered (this solid was mostly boronic acid) and the filtrate solution was concentrated. The residue was purified by flash column chromatography on SiO2 which provided a mixture of desired product and dimethyl 5-bromoisophthalate (3.4 g). This mixture was carried on into the same coupling reaction again repeating the same procedure except it was heated at 77° C. for 16 h. The solid was filtered, washed with EtOAc, and the filtrate solution was washed with water, dried, concentrated, and the residue was passed through a flash column on SiO2 eluting with 3:1/Hex:EtOAc, which provided the desired product (3.0 g, 10.41 mmol, 52%) as a white solid. 1H NMR (CDCl3): δ 8.62 (d, J=1.7 Hz, 1H), 8.39 (d, J=1.7 Hz, 2H), 7.61 (dd, J=8.8, 5.5 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 3.96 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N[C@@H:31]1CCCC[C@H]1CNC1C(F)=CN=C(C2C3C(=NC=C(Cl)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)N=1.CS(Cl)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:31][C@H:20]4[NH:21][S:25]([CH3:28])(=[O:26])=[O:27])[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Reactant: CS(=O)(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: CS(=O)(=O)Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F

Procedure:
Sulfonamide 557 was prepared according to the procedure for compound 36 (Scheme 12B) using N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, and methane sulfonyl chloride, afforded desired product, 557, as a racemic mixture of trans isomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>ClCCl.O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 89.1 %

Procedure:
To a cold (ice bath) mixture of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 250 mg), 4-chlorophenol (136 mg) and triphenylphoshine (256 mg) in dichloromethane (4 mL) and tetrahydrofuran (1.5 mL) was slowly added a solution of di-tert-butyl-azodicarboxylate (225 mg) in tetrahydrofuran (2.5 mL). The reaction mixture was stirred at room temperature for 2.5 days then concentrated in vacuo and the residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethylacetate (1:0 to 9:1 v/v) as eluant to afford the title compound (0.304 g, 89%) as light yellow oil. MS (EI): 413.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH2:13])=[O:12])[C:5]=2[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.ClCCl.C([BH3-])#N.[Na+]>CO>[CH:5]1([N:18]2[CH2:19][CH2:20][CH:15]([N:3]3[C:4](=[O:14])[C:5]4[C:6]([C:11]([NH2:13])=[O:12])=[CH:7][CH:8]=[CH:9][C:10]=4[CH:2]3[CH3:1])[CH2:16][CH2:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1c2cccc(C(N)=O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 1-methyl-3-oxo-2-(piperidin-4-yl)-2,3-dihydro-1H-isoindole-4-carboxamide (60 mg, 0.19 mmol) in dichloromethane (2 mL) cyclohexanone (147 mg, 0.28 mmol) sodium acetate (32 mg, 0.38 mmol) and methanol (0.3 mL) were added. The resulted solution was stirred at room temperature for 5 hours. Then sodium cyanoborohydride was added and the mixture was stirred overnight. The solvents were removed under reduce pressure and the residue was dissolved in dichloromethane and washed twice with water. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo and the residue was purified by flash chromatography (dichloromethane/methanol: 95:5) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:25]([CH3:27])[CH3:26])[CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1.BrN1C(=O)C[CH2:31][C:30]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl-].[NH4+]>C(Cl)(Cl)(Cl)Cl.O1CCCC1.O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:25]([CH3:27])[CH3:26])[CH2:9][O:10][CH:11]([C:30]#[CH:31])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: C#CC(OCC(c1ccc(Cl)cc1)C(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
3.8 g of 3-phenoxybenzyl 2-(4-chlorophenyl)-2-isopropylethyl ether, 1.8 g of N-bromosuccinimide and a few crystals of azo-bis-isobutyronitrile were stirred under reflux in 80 ml of carbon tetrachloride for 30 minutes. The mixture was cooled in an ice-bath, filtered and the solvent removed to give a pale orange oil. A solution of the oil in 10 ml of tetrahydrofuran was added over a 20 minute period to a solution of an acetylenic Grignard reagent (prepared by saturating a solution of 2.3 g of ethyl bromide and 0.5 g of magnesium in 35 ml of tetrahydrofuran with acetylene at 15° C) whilst bubbling a slow stream of acetylene through the mixture. The stirring was continued overnight at room temperature under a stream of nitrogen. The black reaction mixture was warmed to 70° C for 30 minutes, cooled and a saturated solution of 20 ml of ammonium chloride added, followed by ether and water. The mixture was filtered through a "Celite" bed to remove the black solid and the organic layer separated, washed successively with ammonium chloride, sodium bicarbonate, sodium hydroxide and dried (MgSO4). Removal of the solvent gave a dark brown oil which was purified by chromatography on silica gel using 1:1 toluene: petroleum ether 60°-80° C as eluent, to give 2.
Reaction SMILES: [H-].[Na+:2].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].F[C:36]1[CH:41]=[C:40]([CH2:42][N:43]([CH3:45])[CH3:44])[CH:39]=[CH:38][N:37]=1.[OH-].[Na+]>CN(C=O)C>[CH3:44][N:43]([CH2:42][C:40]1[CH:39]=[CH:38][N:37]=[C:36]([O:28][CH:25]2[CH2:26][CH2:27][CH:22]([N:12]([C:11]3[CH:10]=[C:9]([C:29]#[C:30][C:31]([CH3:32])([CH3:33])[CH3:34])[S:8][C:7]=3[C:5]([O-:4])=[O:6])[C:13]([CH:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)=[O:14])[CH2:23][CH2:24]2)[CH:41]=1)[CH3:45].[Na+:2]
Reactant: CN(C)Cc1ccnc(F)c1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3cc(CN(C)C)ccn3)CC2)CC1
Temperature: 25 °C
Yield: 31 %

Procedure:
NaH (65 mg of a 60% oil dispersion, 1.62 mmol) was added to solution 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (155 mg, 0.34 mmol) and (2-fluoro-pyridin-4-ylmethyl)-dimethyl-amine (130 mg, 0.84 mmol) in DMF (4.0 mL) at 0° C. After 5 min the reaction was warmed to room temperature and then heated at 65° C. for 2 h. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction mixture evaporated to dryness. Purification by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water) provided the desired product as a colorless solid (62 mg, 31%) after lyophilization. MS (m/z): 580.2 [M+H]; HPLC retention time: 5.05 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[N:22]1([C:2]2[C:11]([F:12])=[CH:10][C:9]3[C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]4[C:8]=3[C:3]=2[CH2:4][CH2:5][N:6]4[CH3:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Reactant: C1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2C
Temperature: 80 °C
Yield: 75.9 %

Procedure:
2.92 g of the compound (6) obtained in Example 2 (1), 1.07 g of pyrrolidine and 2.25 g of 1,8-diazabicyclo[5.4.0]-7-undecene were added to 20 ml of N,N-dimethylformamide, and the solution was heated at 80° C. for 12 hours. The solvent was removed by distillation, and 100 ml of chloroform was added to the residue. After washing with water, the organic layer was separated from the solution. After drying over magnesium sulfate, the solvent was removed by distillation. To the residue, 50 ml of isopropyl ether was added, and the solid was filtered to obtain 2.60 g of the subject compound (122).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:22])(=[O:21])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:7]=1[N+:23]([O-:25])=[O:24])C.[OH-].[Na+].Cl>C(O)C>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:22])=[O:21])=[CH:8][C:7]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(=O)Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 83.1 %

Procedure:
To a stirred suspension of (4-Benzylsulfamoyl-2-nitro-phenyl)-carbamic acid ethyl ester (1.50 g, Reference Example 62) in ethanol (30 ml) was added 2M sodium hydroxide solution (5.93 ml) and the reaction heated at 75° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured onto ice-water and acidified to pH3 with 2M hydrochloric acid (30 ml). The resultant precipitate was collected by filtration and dried in vacuo to give 4-amino-N-benzyl-3-nitro-benzenesulfonamide (1.01 g) as a yellow solid. LC-MS (METHOD J): RT=3.41 minutes, 308.22 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:26])[NH:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1)([CH3:17])([CH3:16])[CH3:15]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([N:20]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)[C:19](=[O:26])[O:18][C:14]([CH3:17])([CH3:15])[CH3:16])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F

Procedure:
The above titled compound was prepared from 2,4,5-trifluorobenzenesulfonyl chloride (5.0 g, 0.022 mol) and thiazole-4-yl-carbamic acid tert-butyl ester (Preparation 72, 4.3 g, 0.022 mol) using the method of Preparation 453 to afford the product as a white solid (6.84 g, 80%).
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[ClH:3].[CH3:24][C:25]([CH3:28])=[CH:26][CH2:27][NH:14][C:28]([C:25]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]3[CH2:10][CH2:9][CH2:8][CH2:7]3)[C:27]=2[CH:26]=1)=[O:30]
Reactant: O=S(Cl)Cl
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Agent: Cl
Solvent: ClCCl
Product: CC(C)=CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
Thionyl chloride (0.5 cc) is introduced during 5 minutes and with stirring into a suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (1 g) in methylene chloride (30 cc) while the temperature is maintained in the vicinity of 5° C. Stirring is continued for 40 minutes while heating to a temperature in the region of 30° C., and the yellow solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4kPa) at 40° C. The residue is dissolved in methylene chloride (30 cc) and 3-methyl-2butenylamine (0.73 g) and triethylamine (0.84 cc) are added. Stirring is maintained for 30 minutes at 20° C. The reaction mixture is diluted with ethyl acetate (100 cc), washed successively with N aqueous sodium hydroxide solution (50 cc) and then with saturated aqueous sodium chloride solution (2×50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily orange residue (0.9 g) is dissolved in a mixture (30:70 by volume) (35 cc) of ethyl acetate and isopropyl ether, and a 0.3N solution (5.5 cc) of hydrochloric acid in isopropyl ether is added with stirring at 6° C. After one hour's stirring at 6° C., the solid formed is filtered off, washed with isopropyl ether (5 cc) and dried under reduced pressure (5 mm Hg; 0.67 kPa) at 40° C. to give N-(3-methyl-2-butenyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.52 g) in the form of a cream-coloured solid, m.p. about 150° C.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]([NH2:14])[CH3:13].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.CCOC(C)=O.CCO.CCOCC>[ClH:1].[ClH:1].[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)[CH3:13]
Reactant: O=C(O)c1cccnc1
Reactant: CC(N)c1cc2ccncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1cccnc1)c1cc2ccncc2[nH]1
Reaction time: 18 h
Yield: 22.1 %

Procedure:
A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethylamine dihydrochloride (Example 75) (74 mg, 0.32 mmol), nicotinic acid (41 mg, 0.33 mmol), diisopropylethylamine (0.28 mL, 0.38 mmol), EDCI (73 mg, 0.38 mmol) and dimethylaminopyridine (catalytic amount) in methylene chloride (2.8 mL) was stirred under a nitrogen atmosphere overnight (18 h). The reaction mixture was diluted with EtOAc and extracted with 1 N HCl. The acidic extracts were washed with EtOAc, and then made basic with 15% NaOH. The aqueous layer was extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4. Filtration and concentration gave a crude yellow oil. Initial purification by Biotage chromatography (KP-NH silica) provided an impure product. The mixture was dissolved in EtOH and 2.0 M HCl in Et2O (0.34 mL) was added. The mixture was concentrated and then crystallized from acetone/methanol (9:1) to provide N-[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl]nicotinamide dihydrochloride (12 mg, 11%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ3.64 (3H, d, J=7.1 Hz), 5.65 (1H, q, J=7.0 Hz), 6.98 (1H, s), 8.03-8.20 (3H, m), 8.94-9.02 (3H, m), 9.34 (1H, s); ESI MS m/z 267 [C15H14N4O+H]+; HPLC (Method A) >99% (AUC), tR=9.19 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.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>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Clc1ccnc2cccnc12
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: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cc(-c2ccnc3cccnc23)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
(Some starting materials may be obtained from Aldrich, St. Louis, Mo.) To a 50 mL round-bottomed flask was added 4-chloro-1,5-naphthyridine (40 mg, 243 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (100 mg, 243 μmol), tetrakis(triphenylphosphine)palladium (28 mg, 24 μmol), sodium carbonate (243 μl, 486 μmol), dioxane (2 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (3 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 70% EtOAc/hexanes to give N-(2-chloro-5-(1,5-naphthyridin-4-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (46 mg, 46% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H12ClFN4O2S: 414.0; found 415.0. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.09 (s, 1 H) 7.13-7.23 (m, J=8.33 Hz, 2 H) 7.68 (d, J=4.38 Hz, 1 H) 7.75 (dd, J=8.55, 4.17 Hz, 1 H) 7.97 (dd, J=8.99, 4.90 Hz, 2 H) 8.49-8.56 (m, J=2.85, 2.85 Hz, 2 H) 8.58 (d, J=2.05 Hz, 1 H) 9.01 (dd, J=4.17, 1.68 Hz, 1 H) 9.10 (d, J=4.38 Hz, 1 H)
Reaction SMILES: CO[CH:3](OC)[CH2:4]Cl.C([O-])(=O)C.[Na+].[NH2:13][C:14]1[N:19]([CH3:20])[C:18](=[O:21])[N:17]([CH3:22])[C:16](=[O:23])[CH:15]=1>O>[CH3:20][N:19]1[C:14]2[NH:13][CH:3]=[CH:4][C:15]=2[C:16](=[O:23])[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Reactant: COC(CCl)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2cc[nH]c2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
To a stirred solution of chloroacetaldehyde dimethyl acetal (26.0 g, 208.717 mmol) in water (60 mL) concentrated hydrochloric acid (4 mL) was added at room temperature and the reaction mixture was stirred at near boiling until a homogeneous solution was obtained. Solution of sodium acetate (8.0 g, 97.525 mmol) was then added. The resulting mixture was then added to a stirred solution consisting of 6-amino-1,3-dimethyl uracil (20.0 g, 128.907 mmol) and sodium acetate (16.0 g, 195.051) in water (100 mL) at 90° C. All solid material was dissolved, then after 10 min. a precipitate was started to form. The reaction mixture was stirred for another 30 min. at the same temperature. The reaction mixture was cooled to room temperature and solid obtained was filtered, washed with water (2×250 mL) and then acetone (2×150 mL). The solid obtained was dried in oven at 65° C. to obtain 7.81 g of the product as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.20 (s, 3H), 3.42 (s, 3H), 6.35 (s, 1H), 6.77 (s, 1H), 11.71 (br s, 1H); APCI-MS (m/z) 180.25 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCOCC>[CH2:1]([N:8]1[CH2:9][C@@H:10]([CH3:15])[NH:11][C@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C(=O)[C@@H](C)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)C[C@@H](C)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
a solution of (R,R) 1-benzyl-3,5-dimethylpiperazine-2-one (1.3 g) in THF (10 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.68 g) in THF (30 ml) at 0° C. under Ar. The mixture was stirred for 30 min then heated under reflux for a further 18 h. The mixture was cooled to 0° C. and diluted with ether (50 ml). To the stirred mixture were added water (2 ml) sodium hydroxide solution (2 ml) and water (2 ml). The mixture was stirred for 1 h then filtered through a pad of kieselguhr, washing with DCM. The filtrate was concentrated in vacuo to give the product as a clear oil (0.99 g); δH (400 MHz, CDCl3) 7.35–7.20 (5H, m), 3.48 (1H, d, J 13 Hz), 3.38 (1H, d, J 13 Hz), 3.19 (1H, m), 2.49 (2H, dd, J 10.5, 3 Hz), 2.09 (2H, dd, J 10, 6.5 Hz) and 1.14 (6H, d, J 6.5 Hz); LC 93%, 1.91 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:24][CH3:25])[N:10]=[CH:9][N:8]=[C:7]2[NH:6][C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([Cl:2])[C:4]=1[F:29])(=[O:32])[CH3:31]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@H]1CCCN1C(C)=O
Yield: 66 %

Procedure:
Using a procedure similar to that described in Example 38, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (300 mg; prepared as described in Example 32-preparation of starting materials) was reacted with acetic anhydride to give the title product (203 mg, 66%); 1H NMR Spectrum (DMSO d6) 1.89-2.05 (m, 6H); 2.11-2.21 (m, 1H); 3.43-3.56 (m, 2H); 3.94 (s, 3H); 4.00-4.11 (m, 1H); 4.17-4.21 (m, 1H); 4.30-4.37 (m, 1H); 7.19-7.29 (m, 2H); 7.42-7.53 (m, 2H); 7.79-7.82 (m, 1H); 8.37 (s, 1H); 9.54-9.57 (m, 1H); Mass Spectrum (M+H)# 445.