Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C@H:14]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:13][C@H:14]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:11])=[O:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3cc(Cl)ccc3Cl)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 2,5-dichlorobenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 588.0 (M+H)+.
Reaction SMILES: [N+:1](/[CH:4]=[C:5]1\[NH:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][CH2:11]\1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][CH2:11][CH:5]1[CH2:4][NH2:1]
Reactant: O=[N+]([O-])/C=C1/CCCc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCCc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 182D (0.643 g, 3.15 mmol) in tetrahydrofuran (31.5 mL) under argon was added dropwise lithium aluminum hydride in tetrahydrofuran (9.45 mL, 18.89 mmol), and the mixture was stirred at room temperature for 30 minutes. Water was added carefully and the mixture was extracted once with dichloromethane. The organic extract was dried over Na2SO4, and the solvent was evaporated to obtain the crude title compound which was used was used without purification for the next reaction. MS (ESI+) m/z 177.3 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:31])=[O:9])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=1
Reactant: COc1ccc2cc(-c3ccc(SC)cc3)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(S(C)=O)cc3)ccc2n1
Temperature: 25 °C

Procedure:
A solution of m-chloroperbenzoic acid (0.56 g) in dichloromethane (5 cm3) was added dropwise at -70° to a stirred solution of 2-methoxy-6-[4-methylthiophenyl]quinoline (0.7 g) in dichloromethane (10 cm3). The mixture was warmed to room temperature over 1 hour, taken into dichloromethane (25 cm3) and washed with sodium carbonate solution (10 cm3). The organic phase was dried (MgSO4) and evaporated and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform:methanol, 19:1. The appropriate fractions were combined and evaporated to give a solid which was recrystallised from acetone-hexane to afford the title compound, m.p. 163.5°-165.5°, (0.55 g).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:12])=[O:6])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccccc1C=O
Temperature: 25 °C

Procedure:
6 Grams of 2-formylbenzoic acid and 6 g of potassium carbonate were added to 30 ml of dimethylformamide, then 6 g of methyl iodide were added dropwise thereto at room temperature with stirring. The reaction mixture was continuously stirred at room temperature overnight, then was concentrated. The residue obtained was extracted with chloroform, and the chloroform layer was washed with water, and was dried with anhydrous magnesium sulfate, then concentrated. The residue obtained was purified by distillation under reduced pressure to yield 3 g of methyl 2-formylbenzoate. Boiling point: 95° C. (at 0.5 mm-Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[B:10]([OH:12])[OH:11].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[B:10]([OH:12])[OH:11]
Reactant: O=Cc1ccc(Cl)c(B(O)O)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: OB(O)c1cc(CN2CCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (2-chloro-5-formylphenyl)boronic acid (1.00 g, 5.42 mmol) in DCM (30 mL) were added pyrrolidine (0.45 mL, 5.42 mmol) and sodium triacetoxyborohydride (2.39 g, 11.3 mmol). The reaction mixture was allowed to stir at rt for 2.5 h and then diluted with brine. The mixture was extracted with DCM. The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give [2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]boronic acid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13](O)=[O:14])=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:30]=[CH:31][C:32]=1[CH3:33]>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([NH:26][C:13]([C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][C:6]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)=[N:7][C:8]=23)=[O:14])[CH:28]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1N
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B. 11) according to general procedure II. Pale-yellow solid. Mp 232-233° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([S:12][CH2:13][CH3:14])=[CH:8][C:7]2=[O:15].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24].[CH3:29][C:30](N(C)C)=O>O.C(OCC)(=O)C>[F:20][C:21]1[CH:22]=[C:23]([NH:24][CH:29]([C:2]2[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]3[C:11]=2[O:10][C:9]([S:12][CH2:13][CH3:14])=[CH:8][C:7]3=[O:15])[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CCSc1cc(=O)c2cc(C(=O)OC)cc(Br)c2o1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1cc(=O)c2cc(C(=O)OC)cc(C(C)Nc3cc(F)cc(F)c3)c2o1
Yield: 57 %

Procedure:
Methyl 8-bromo-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (850 mg, 2.29 mmol, prepared as described in Example 9) and 3,5-difluoroaniline (621 mg, 4.81 mmol) in DMA (10 mL) were stirred at 50° C. overnight. The reaction mixture was diluted with water/ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 25% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (550 mg, 57%) as a off-white solid. Mass Spectrum: M+H+ 420. SNH
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[O:12][CH:7](OC(=O)C)[C@H:6]([O:13][C:14](=[O:16])[CH3:15])[C@@H:5]1[O:17][C:18](=[O:20])[CH3:19].[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24]([Cl:31])[N:23]=1>C(Cl)(Cl)Cl>[C:14]([O:13][C@@H:6]1[C@H:5]([O:17][C:18](=[O:20])[CH3:19])[C@@H:4]([CH2:3][O:2][CH3:1])[O:12][C@H:7]1[N:28]1[CH:27]=[N:26][C:25]2[C:29]1=[N:30][C:22]([Cl:21])=[N:23][C:24]=2[Cl:31])(=[O:16])[CH3:15]
Reactant: COC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: ClC(Cl)Cl
Product: COC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
5-O-Methyl-1,2,3-tri-O-acetyl-D-ribofuranose (5.0 g, 17 mmol) and 2,6-dichloropurine (3.3 g, 17 mmol) were thoroughly mixed. A catalytic amount of p-toluene sulfuric acid (50 mg) was added and the reaction mixture was heated to 140° C. at which point a homogeneous melt was obtained. The fusion was continued at 140° C. under oil pump vacuum for 0.5 h. The reaction mixture was dissolved in chloroform (200 ml) and washed with aqueous sodium bicarbonate (3×50 ml) and water (2×50 ml). The organic phase was dried (MgSO4), evaporated in vacuo and purified by flash chromatography eluting with a mixture of n-heptane and ethyl acetate (1:1) to provide 9-(2',3'-di-O-acetyl-5'-O-methyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g, 14%) as an oil which crystallized from diethyl ether. A mixture of α/β-anomers (1.2 g, 17%) was also isolated, with mp 59°-61° C. 1H-NMR (400 MHz,CDCL3) δ2.06 (3H, s, --OCOCH3), 3.49 (3H, s, OCH3), 3.67, 3.72 (2H, ABX, H-5'a and H-5'b), 4.39 (1H, d, H-4'), 5.58 (1H, d, H-3'), 5.75 (1H, t, H-2'), 6.38 (1H, d, H-1'), 8.56 (1H, s, H-8). C15H16Cl2N4O6 requires C, 43.0; H, 3.9; N, 13.4. Found C, 43.1, H, 3.9, N, 13.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.74 g, 0.002 mol) in DMF (10 mL), was added 3-methoxybenzyl bromide (0.47 g, 0.0023 mol) and powdered and potassium carbonate (1.93 g, 0.014 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.81 g in 77% yield. 1H NMR (CDCl3) δ 7.19 (s, 1H), 7.17 (m, 11H), 7.09 (t, 1H), 6.83 (d, 1H), 6.72 (t, 2H), 6.59 (m 2H), 4.19 (t, 1H), 3.72 (s, 6H), 3.61 (s, 4H), 3.55 (d, 2H), 3.07 (d, 2H), 2.62 (t, 2H), 1.82 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.9, 160.6, 144.9, 142.8, 136.6, 130.8, 130.3, 129.9, 129.7, 129.6, 127.6, 122.7, 122.6, 116.9, 115.2, 114.5, 114.3, 67.0, 61.2, 60.6, 56.4, 51.9, 51.2, 42.7, 28.2.
Reaction SMILES: C(N[C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15](=O)[C:16](Cl)=[O:17])=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)(=O)C.Cl.C([O:24][C:25](=[NH:40])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([N+:36]([O-:38])=[O:37])=[CH:33][CH:34]=2)[N:29]([CH3:39])[CH:28]=1)(C)C>>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][CH:13]=2)[C:9]([NH:40][C:25](=[O:24])[CH3:26])([C:15]2[C:16](=[O:17])[NH:24][C:25](=[O:40])[C:26]=2[C:27]2[C:35]3[C:30](=[CH:31][C:32]([N+:36]([O-:38])=[O:37])=[CH:33][CH:34]=3)[N:29]([CH3:39])[CH:28]=2)[CH2:10]1
Reactant: CC(=O)Nc1ccc2c(C(=O)C(=O)Cl)cn(C)c2c1
Reactant: CC(C)OC(=N)Cc1cn(C)c2cc([N+](=O)[O-])ccc12
Agent: Cl
Product: CC(=O)NC1(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)CN(C)c2ccccc21

Procedure:
ss) N-{1-Methyl-3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indol-3-yl}-acetamide was prepared from (6-acetylamino-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-6-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=O)[NH:8][CH2:7][CH2:6]2.CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(=O)NCC2
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Yield: 83.9 %

Procedure:
A solution of 6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-isoquinolinone (7 g, 31.5 mmol) in THF (800 mL) was treated with 2M BH3 in THF(78.8 mL, 157.6 mmol) and heated to reflux for 20 h. Methanol (100 mL) was added and the solution was concentrated under reduced pressure. The resulting residue was heated with 2N HCl for 3 hr., cooled, basified via careful addition of aqueous ammonium hydroxide, and extracted with dichloromethane. The organic layer was dried, filtered, and taken to a residue under reduced pressure to afford 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (5.5 g crude, 84.5% pure).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10](=O)[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O>[CH2:1]([O:3][C:4]1[C:9]2[C:10](=[N:20][OH:21])[CH2:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CCOc1cccc2c1C(=O)CO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cccc2c1C(=NO)CO2
Temperature: 23 °C
Yield: 93 %

Procedure:
A mixture of 4-ethoxy-benzofuran-3-one (CAS no: 7169-36-0) (4.18 g, 23.5 mmol), sodium acetate (3.96 g, 48.3 mmol) and hydroxylamine hydrochloride (3.34 g, 48.1 mmol) in ethanol (30 mL) was refluxed for 16 h. Cooled to 23° C., diluted with water (50 mL), filtered the precipitate off, washed with water, ethanol and diethyl ether and dried in high vacuum to give the title compound as a white solid (4.2 g, 93%); MS: m/e=194.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27]>ClCCl.N1C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([S:28]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)c1ccc(F)c(F)c1
Yield: 35.8 %

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with 3,4-difluorobenzenesulfonyl chloride (0.061 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) to obtain 0.015 g (36%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([S:12][C:13]#[N:14])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=C)[CH3:2].[BrH:15].C(O)(=O)C.O>C(O)(=O)C>[Br:15][C:13]1[S:12][C:3]([CH2:1][CH3:2])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:14]=1
Reactant: C=C(c1ccccc1)C(CC)SC#N
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: CCc1sc(Br)nc1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 1-ethyl-2-phenylprop-2-en-1-yl thiocyanate (4.15 g, 20.2 mmol) in acetic acid (40 ml) was added a 25% hydrogen bromide/acetic acid (40 ml) solution, and the mixture was stirred at 130° C. for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (4.02 g, 74.2%) as an oil.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.C[N:19]([CH:21]=O)C.[C-:23]#[N:24].[Na+].CN>C(Cl)Cl>[C:23]([C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:19][CH3:21])=[O:15])#[N:24]
Reactant: CN(C)C=O
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Agent: CN
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Temperature: 85 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A 50 gallon reactor was charged with 16.6 kg (66.3 mol) of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester and 40 l. of DMF. To the stirred solution was added 6.5 kg (132.6 mol) of sodium cyanide and the resulting reaction mixture was heated at 85° C. for 5 hours. The mixture was allowed to stir overnight at room temperature. A thin layer chromatograph in methylene chloride of a sample of the reaction mixture indicated the presence of a small amount of starting material. the reaction mixture was heated to 100° C. for 2 hours and cooled. The mixture was charged with 18 kg (232 mol) of 40% aqueous methylamine. The mixture was stirred at room temperature overnight and 40 l. of ice water was added. The mixture was stirred at about 10° C. for one hour using a cooling jacket and the precipitated solid was collected by filtration. The solid was washed with water several times and dried to provide 12.4 kg of 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. Yield 82.7%. Purity of this material by HPLC was 98.14%. mp=203°-205° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9])#[N:12]
Reactant: Nc1c(F)cccc1F
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: N#CN=C(N)Nc1c(F)cccc1F

Procedure:
2,6-Difluoroaniline and sodium dicyanamide were procesed as described in Example 71A to provide the desired compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)=S.[N:15]#[C:16][NH2:17].[Pb]>>[C:16]([NH:17][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)#[N:15]
Reactant: N#CN
Reactant: CNC(=S)NCCSCc1ccon1
Agent: [Pb]
Product: CNC(=NCCSCc1ccon1)NC#N

Procedure:
Reaction of N-methyl-N'-[2-(3-isoxazolylmethylthio)-ethyl]thiourea with lead cyanamide by the procedure of Example 121 gives N-cyano-N'-methyl-N"-[2(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: Cc1nc(NC(=O)c2cc(F)cc(F)c2)sc1C(=O)NCc1ccccc1
Yield: 48 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3,5-difluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 48% yield; m.p. 84-86° C.; 1H NMR (CDCl3, 300 MHz) δ 7.44-7.24 (m, 7H), 7.01 (tt, J=2.2, 8.4 Hz, 1H), 6.05 (s, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.41 (s, 3H); MS (ES+) m/z 388.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=[C:7]1[CH:6]=[CH:5]2.Cl>C(O)C.[OH-].[Na+].O>[OH2:16].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=[C:7]1[CH:6]=[CH:5]2
Reactant: CCOC(=O)c1cn2c(ccc3cc(Cl)ccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(ccc3cc(Cl)ccc32)n1

Procedure:
820 mg of ethyl 7-chloroimidazo-[1,2-a]-quinoline-2-carboxylate in 25 ml of ethanol and 1 N sodium hydroxide solution was added thereto. The mixture obtained was heated on a steam bath for 30 minutes and then was diluted with 50 ml of water. The mixture was neutralized with 3.5 ml of 2 N hydrochloric acid and then cooled to obtain pale cream crystals of 7-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid monohydrate melting at 278°-279° C. The I.R. spectrum suggests that the compound exists at least partially in the zwitterionic form.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:28])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19](=[N:23]C(C)(C)C)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:29]([C:38](OC)=[O:39])([C:34](OC)=[O:35])[C:30]([O:32][CH3:33])=[O:31]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:28])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[NH:23][C:34](=[O:35])[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:38]([OH:39])[C:20]=1[CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1c(-c2ccc3c(c2)cc(CO[Si](C)(C)C(C)(C)C)n3C)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 230 °C
Yield: 21.2 %

Procedure:
To a solution of N-(1-(2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indol-5-yl)butylidene)-2-methylpropan-2-amine (2.10 g, ca. 5.2 mmol), prepared according to procedure described in Example 39 Step 5, in Ph2O (5 mL) was added trimethyl methanetricarboxylate (1.68 g, 8.8 mmol, 1.7 eq). The mixture was heated to 230° C. for 2 h. The mixture was cooled to room temperature then purified by flash column chromatography (0-50% EtOAc in CH2Cl2) to afford the title compound (0.51 g, 1.1 mmol, 21%) as a light yellow solid. LC-MS 469.2 [M−H]−, 471.2 [M+H]+, RT 1.67 min.
Reaction SMILES: [NH2:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][NH:4][C:3]1=[O:6].N1C=CC=CC=1.[C:24](OC=O)(=[O:26])C>ClCCl>[CH:24]([NH:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][NH:4][C:3]1=[O:6])=[O:26]
Reactant: CC(=O)OC=O
Reactant: NC1(NC(=O)COc2ccccc2)CNC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CNC1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
The amine (27) (66 mg) in dry dichloromethane (5 ml) was cooled to 0° and treated with pyridine (49 mg) followed by formic-acetic anhydride (27 mg). The mixture was stirred at 0° for 15 minutes then allowed to warm to room temperature over 15 minutes, and evaporated to dryness. The residue was chromatographed on silica gel to give the product (28) (53 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10](NC)[O:9][N:8]=2)=[CH:4][CH:3]=1.[CH:14]([N:17](C(C)C)CC)(C)C.CO.Cl[CH:26](Cl)[C:27](=[N:29][NH:30]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:28]>C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:14][N:17]3[CH:26]=[C:27]([CH3:28])[N:29]=[N:30]3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CNC1CC(c2ccc(Br)s2)=NO1
Reactant: CC(=NNS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cn(CC2CC(c3ccc(Br)s3)=NO2)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
[3-(5-Bromo-thien-2-yl)-4,5-dihydro-isoxazol-5-yl]-methylamine (2.2 g, 8.4 mmol) and diisopropylethylamine (7.3 ml, 42 mmol) were added to anhydrous methanol (50 ml) followed by addition of N′-[2,2-dichloro-1-methylethylidene]-4-methylbenzenesulfonohydrazide (3.2 g, 10.9 mmol). The reaction was stirred at room temperature for four hours and then ethyl acetate was added. The precipitate was collected and washed with water (2×25 ml) to give the desired product (793 mg).