Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:13]=[C:12]([CH2:14][C:15]([NH:17][CH:18]([CH2:31][OH:32])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:16])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[H-].[Na+].[CH2:35](I)[CH3:36].[CH2:38]([OH:40])[CH3:39]>O1CCCC1>[CH2:38]([O:40][C:3]1[CH:13]=[C:12]([CH2:14][C:15]([NH:17][CH:18]([CH2:31][O:32][CH2:35][CH3:36])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:16])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:39]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)cc1CC
Reactant: CCO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Reaction time: 1 h

Procedure:
Ethyl 2-ethyl-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.64 g, 1.4 mmol) is added with stirring at ambient temperature to sodium hydride (0.061 g, 1.4 mmol) (55% in oil) in absolute tetrahydrofuran (6.4 ml). The mixture is stirred for 1 hour, then ethyl iodide (0.113 ml, 1.4 mmol) is added and the mixture is stirred for a further 16 hours at ambient temperature. Then ethanol (2 ml) is added and the mixture is evaporated down in vacuo. The evaporation residue is partitioned between chloroform and water. The organic phase is washed twice with water, dried, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone=17/3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=S)[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N:26]#[C:27][NH2:28].[Na].[C:30]1([CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][NH2:45])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCO.C1COCC1.Cl[Hg]Cl>[C:27]([N:28]=[C:19]([NH:18][C:14]1[CH:13]=[C:12]([N:6]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]([CH3:25])=[C:5]2[C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][CH:15]=1)[NH:45][CH2:44][CH2:43][CH2:42][N:39]1[CH2:38][CH2:37][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:41][CH2:40]1)#[N:26]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Reactant: NCCCN1CCC(c2ccccc2)CC1
Reactant: N#CN
Agent: Cl[Hg]Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=NC#N)NCCCN2CCC(c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-isothiocyanatophenyl)-3,5-pyrazinedicarboxylic acid, dimethyl ester (144 mg, 0.40 mmol) was added into sodium cyanamide (28 mg, 0.44 mmol) in 3 mL of EtOH and the mixture was stirred for 20 minutes. EtOH was then removed in vacuo and the resultant foam-like material was mixed with 4-phenyl-piperidine-1-propanamine (105 mg, 0.48 mmol) in 5 mL of THF. The mixture was cooled down to 0° C. and HgCl2 (109 mg) was added. The reaction was completed in 15 min. After filtration and extraction, the organic layer was concentrated and purified by chromatography (silica gel, eluted with 10% (v/v) methanol in methylene chloride) to yield the title compound as isolated as a yellow foam (175 mg, 75%); 1H-NMR (CDCl3) δ 7.05-7.35 (m, 6H), 6.75 (br, 1H), 6.65 (d, 1H, J=7.5 Hz), 6.58 (d, 1H, J=8.3 Hz), 6.53 (br, 1H), 5.98 (br, 1H), 3.72 (s, 6H), 3.38 (m, 2H), 2.97 (m, 2H), 2.30-2.55 (m, 3H), 2.39 (s, 6H), 2.03 (m, 2H), 1.65-1.80 (m, 4H), 1.40-1.60 (m, 2H); 13C-NMR (CDCl3) δ 166.2, 152.6, 149.4, 129.9, 128.5, 126.9, 126.3, 118.3, 116.3, 112.5, 110.4, 108.7, 54.1, 51.8, 42.4, 41.0, 32.7, 29.8, 25.6, and 17.9.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[H-].[Na+].[H][H].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20]>CN(C)C=O>[C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O:5][CH2:15][C:16]1[CH:30]=[CH:29][CH:28]=[C:18]([C:19](=[O:20])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:17]=1)=[O:4]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: [H][H]
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)OCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of 28 g of ethyl malonate in 28 ml of dimethylformamide was added to a suspension of 8.4 g of sodium hydride in 260 ml of dimethylformamide at a temperature of 10° to 15° C and the temperature was allowed to return to room temperature. After evolution of 3.9 liters of hydrogen, the resulting solution was poured into a suspension of 52.5 g of 3-bromomethyl-4'-chlorobenzophenone (French BSM No. 8440 M) in 400 ml of dimethylformamide at 24° C. The mixture was stirred for 2 hours and was then evaporated to dryness under reduced pressure. The residue was taken up in 500 ml of water and 75 ml of isopropyl ether and the organic phase was decanted. The aqueous phase was extracted with isopropyl ether and the combined organic phases were dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 63 ml of isopropyl ether with agitation, was iced and crystallization was started. After being iced overnight, the mixture was vacuum filtered and the precipitate was washed with isopropyl ether. The mother liquors were evaporated to dryness to obtain 48.7 g of ethyl 3-(p-chlorobenzoyl)-benzyl malonate which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:6][NH:5][C@H:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])=[N:9]2)[CH2:3]1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C@@H:4]3[CH2:3][C:2]([F:1])([F:32])[CH2:6][N:5]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][C:19]=3[F:31])[C:11]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@@H]1CC(F)(F)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: N#CCC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of 1-[[(2S)-4,4-difluoropyrrolidin-2-yl]methyl]-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (850 mg, crude), 2-cyanoacetic acid (120 mg, 1.31 mmol, 1.29 equiv) and TEA (650 mg, 6.45 mmol, 5.00 equiv) in dichloromethane (30 mL), was added HATU (500 mg, 1.32 mmol, 1.29 equiv). The resulting solution was stirred at room temperature overnight. The mixture was diluted with DCM, washed with HCl (2N), sat. NaHCO3, brine, dried over sodium sulfate and concentrated. The residue was submitted to chromatography (SiO2, DCM:MeOH=30:1) to give 0.4 g (77%) of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidin-1-yl]-3-oxopropanenitrile as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[OH-].[Na+].C(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:19])[F:20])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(-c2ccc(Cl)cc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Cc1c(C(=O)O)c[nH]c1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of methyl 5-[4-chloro-2-(trifluoromethyl)phenyl]-4-methyl-1H-pyrrole-3-carboxylate (0.39 g, 1.3 mmol) in methanol (5.0 ml) was added 5N NaOH (5.0 ml) and the mixture was stirred at 80° C. for 3.0 h. The reaction mixture was cooled to room temperature and added formic acid (3.0 ml). The mixture was concentrated on a rotary evaporator. To the residue was added water and triturated. The solid was filtered and dried to give the title compound (0.37 g, 93%) as a brown solid.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=1)#[CH:2].CO[C:11](=[O:29])[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:15](Cl)=[N:14][CH:13]=1.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37]>>[OH:37][C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:11](=[O:29])[C:12]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)[C:15]([CH2:2][CH2:1][C:3]2[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=2)=[N:14][CH:13]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C#Cc1cncn1C
Product: Cn1cncc1CCc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 140, using 5-ethynyl-1-methyl-1H-imidazole (CAN 71759-92-7), 6-chloro-5-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester, and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials, LC at 215 nm; Rt 3.11: 100%, m/z (ES+): 473.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[CH2:23]=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][OH:24])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=1[F:15])=[O:8]
Reactant: O=C(c1cc(Cl)ccc1-n1ccnc1)c1c(F)cccc1F
Reactant: C=O
Product: O=C(c1cc(Cl)ccc1-n1ccnc1CO)c1c(F)cccc1F

Procedure:
In the manner given in Example 1, 5-chloro-2',6'-difluoro-2-(imidazol-1-yl)benzophenone is heated in a bomb to 150° C. with 37% aqueous formaldehyde solution to give 5-chloro-2',6'-difluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:28][C:29](Cl)=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[C:29](=[O:30])([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCOC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.988 g. of chloroformic acid n-hexyl ester as in Example 1. The 1.675 g. of yellowish, turbid, partially crystallized oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 80 g. of silica gel. Benzene elutes 1.530 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-hexyl carbonate obtained melts at 87.1°-87.5° and is liquid crystalline (monotrope) upon cooling to 62.7°. UV (EtOH): ε270 = 26,300.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](C1C=CNC=1Br)=[O:5].C[O-].[Na+].[CH3:19][N:20]([CH:22]=O)C.[CH:24]1C=CC=C[CH:25]=1>>[CH:22]1[N:20]2[C:19]([O:1][C:2]3[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=3[C:4]2=[O:5])=[CH:25][CH:24]=1
Reactant: CN(C)C=O
Reactant: c1ccccc1
Reactant: O=C(c1ccccc1O)c1cc[nH]c1Br
Agent: C[O-]
Agent: [Na+]
Product: O=c1c2ccccc2oc2cccn12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (2-hydroxybenzoyl)-2-bromopyrrole (0.26 g, 1.0 mmol, from Example C) in 5 mL of dry benzene at room temperature in an atmosphere of nitrogen, was added sodium methoxide (60 mg, 1.1 mmol). After 5 min, CuBr (22 mg, 0.15 mmol) and DMF (5 mL) were added. The reaction mixture was stirred at room temperature for 1 hr, and then stirred at 100° C. overnight. The solvent was removed in vacuo, and 30 mL of CH2Cl2 was added. The solution was washed with sat. aq. NaHCO3, water, and brine. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by chromatography, using EtOAc-Hex (5:95) as the eluent, to give 51.8 mg of the title compound: mp 129-130° C. 1H NMR (CDCl3) δ 8.28 (1 H, dd, J=6.8, 1.8), 7.76-7.67 (1 H, m), 7.40-7.25 (3 H, m), 6.49 (1 H, t, J=3.5), 5.88 (1 H, dd, J=3.5, 1.8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]=12.C(N(CC)CC)C.CCOCC>C(O)C>[Cl:17][C:15]1[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]2=[C:11]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=1
Reactant: COc1cccc(N)c1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
m-Anisidine (1.1 eq) was added to a solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 (1 eq.) and triethylamine (NEt3, 1.5 eq) in ethanol. The mixture was stirred at room temperature for 2 hr and then ether was added. The solid was filtered off and the filtrate concentrated in vacuo to give 6-chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][N:8]=[C:9]([C:35]2[N:36]=[C:37]([NH:40]C=O)[S:38][CH:39]=2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[N:2]1.Cl.CO>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][N:8]=[C:9]([C:35]2[N:36]=[C:37]([NH2:40])[S:38][CH:39]=2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[N:2]1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccon3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccon3)c3csc(N)n3)[C@H]2SC1
Yield: 45.3 %

Procedure:
A mixture of 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g), conc.hydrochloric acid (0.497 g), methanol (15 ml) and tetrahydrofuran (3 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(3-isoxazoly)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.65 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Br:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:23]([NH2:37])=[CH:24][C:25]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27][C:26]=2[CH:36]=1.Cl>C(O)CCC.O1CCOCC1>[Br:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:37][C:23]2[C:22]([O:21][CH3:20])=[CH:36][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Br
Yield: 25 %

Procedure:
2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide (52 mg, 0.15 mmol) and 8-methoxy-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (48 mg, 0.19 mmol) were combined in 5 mL n-butanol. Two drops of a solution of 4N hydrochloric acid in dioxane was added and the mixture was refluxed for eight hours. The mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated, was dried (sodium sulfate), and was concentrated to afford an oil which was purified on silica (methanol:dichloromethane gradient elution) to afford 2-{5-bromo-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a tan foam (25%). Mp: 171-5° C.; MS: 556.78 (M+H); 1H NMR (chloroform-d): δ 10.81 (s, 1H), δ 8.60 (d, J=8 Hz, 1H), δ 8.21 (s, 1H), δ 8.08 (s, 1H), δ 7.53-7.41 (m, 3H), δ 6.92 (t, J=8 Hz, 1H), δ 6.66 (s, 1H), δ 6.24 (br s, 1H), δ 3.78 (s, 3H), δ 3.57 (t, J=5 Hz, 35), δ 3.39 (s, 3H), δ 3.06 (dd, J=2.4 Hz, 2H), δ 2.91 (m, 2H), δ 2.82-2.67 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:3]=1.[Li]CCCC.CN(C)[CH:19]=[O:20]>O1CCCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:19]=[O:20])[CH2:9][CH:10]=[CH2:11]
Reactant: CN(C)C=O
Reactant: C=CCCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCc1cccc(C=O)c1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a mixture of 1-bromo-3-(but-3-en-1-yl)benzene (0.5 g, 2.369 mmol) in tetrahydrofuran (10 mL) at −78° C. was added BuLi (1.137 mL, 2.84 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.208 g, 2.84 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 3-(but-3-en-1-yl)benzaldehyde (0.3 g, 79%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.77-7.72 (m, 2H), 7.51-7.46 (m, 2H), 5.86 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.10-5.00 (m, 2H), 2.86-2.79 (m, 2H), 2.48-2.39 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([N:21]1[C:25]([CH:26]=O)=[CH:24][C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([CH2:26][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)=[CH:24][C:23]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: CC(C)Cc1cc(C=O)n(C(C)(C)C)n1
Product: CC(C)Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)n(C(C)(C)C)n1
Yield: 54.8 %

Procedure:
Compound 78 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 2-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14](O)(=O)[CH2:15][CH3:16].Cl>>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:14]([CH2:15][CH3:16])=[N:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: CCC(=O)O
Agent: Cl
Product: CCc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1
Yield: 14.2 %

Procedure:
A mixture of 12.0 g of 2-amino-4-chloro-5-sulfamylaniline, 16.1 g of propionic acid, and 54.4 ml of 4 N hydrochloric acid was refluxed for 6 hours. The solid was collected by filtration, dissolved in boiling methanol, charcoal added, and the solution filtered through Celite. Upon adding to 38% ammonium hydroxide with stirring, a pink solid formed. This was collected by filtration, washed with hot water, air dried, and then recrystallized from acetonitrile to provide 2.0 g of crystals, m.p. 240°-242°.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:20])[N:10]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][CH:24]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:22][C:23]1[C:28]([C:29]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=[C:9]3[NH:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH2:6]2)=[O:30])=[C:27]([F:32])[C:26]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:25][CH:24]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1nc(NC2CCC(C)(C)CC2)c2cccc(N)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC2CCC(C)(C)CC2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 7.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-dimethylcyclohexyl)-2-methylquinazoline-4,8-diamine (Intermediate-47, 180 mg, 0.63 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 271 mg, 0.95 mmol), oxalyl chloride (180 mg, 1.43 mmol), DMF (1 drop) and DIPEA (244 mg, 1.89 mmol) in CH2Cl2 (8 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.66 (d, J=7.8 Hz, 1H), 8.14 (t, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.93 (d, 1H), 7.43 (m, 2H), 7.37 (d, J=7.8 Hz, 1H), 4.31 (d, 2H), 4.17 (m, 1H), 2.44 (s, 3H), 1.72 (m, 2H), 1.64-1.60 (m, 2H), 1.41-1.28 (m, 4H), 1.14 (s, 9H), 0.98 (s, 3H), 0.94 (s, 3H); MS (m/z): 554.35 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C:5]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[OH:40]S(O)(=O)=O.[C:45](#[N:47])[CH3:46]>>[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C:5]([NH:47][C:45](=[O:40])[CH3:46])([CH2:4][CH2:3][C:2]([CH3:38])([CH3:39])[CH3:1])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: O=S(=O)(O)O
Reactant: CC#N
Reactant: CC(C)(C)CCC1(O)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Product: CC(=O)NC1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of the product of Example 74C (1.0 g, 1.8 mmol) in acetonitrile (16 mL) at 0° C. was added conc. H2SO4 (8 mL). The reaction mixture was warmed to room temperature and stirred for 2 h. The solution was poured unto ice (100 g) and extracted with 3:1 dichloromethane:isopropanol (3×50 mL). The organic extracts were combined, dried (Na2SO4), and concentrated in vacuo. The resulting residue was dried under high vacuum to give the title compound as a yellow solid (0.98g, 92%). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.39-0.56 (m, 1H), 0.65 (s, 9H), 0.81-0.98 (m, 1H), 1.77-1.90 (m, 4H), 1.92-2.07 (m, 1H), 6.90-7.04 (m, 2H), 7.39-7.58 (m, 3H), 7.73 (t, J=7.54 Hz, 1H), 8.11 (d, J=7.35 Hz, 1H), 9.16 (s, 1H), 13.38 (s, 1H); MS m/z 497.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15](P(=O)(OC)OC)[O:14]1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13](=[O:12])[O:14]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: N#Cc1cc(C=O)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cc(C=C2OC(=O)c3ccccc32)ccc1F
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To the solution of 2-fluoro-5-formylbenzonitrile (0.74 g, 5 mmol) and dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (1.2 g, 5 mmol) in THF (30 ml) was added triethylamine (0.7 ml, 5 mmol) dropwise at a temperature of below 15° C., which was then slowly rose to ambient temperature and stirred for overnight. The reaction mixture was concentrated and the residue was added water and stirred for 30 min. The precipitated solid was collected by filtration, washed with water, hexane, and ether, and dried in vacuo to afford the target compound (1.2 g, 92.3%) as a light yellow solid (a 50:50 mixture of E and Z isomers), used in next step without further purification.