Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9](N1C=CC(=[N+](C)C)C=C1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1>ClCCl.O>[C:1]([O:5][C:6]([NH:8][S:9]([NH:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)C(C)c1ccc(CN)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 50.9 %

Procedure:
N-(1-(tert-butoxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylmethanaminium (A) (5.81 g, 19.32 mmol) was added to a suspension of ethyl 2-(4-(aminomethyl)phenyl)propanoate (4.0 g, 19.32 mmol) in dichloromethane (40 mL) at room temperature and stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). Combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated to get crude compound, which was purified by column chromatography (silica gel; 100-200 mesh). The product eluted with 20% ethyl acetate in pet ether to yielded ethyl 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoate (3.8 g, 51%) as pale yellow solid.
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[Br:13][C:14]1[CH:15]=[C:16](/[C:20](/[C:28]2[C:29]([C:34]#[N:35])=[N:30][CH:31]=[CH:32][CH:33]=2)=[N:21]\S(C(C)(C)C)=O)[CH:17]=[CH:18][CH:19]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:20]2([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[C:28]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[C:34]([NH2:35])=[N:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccnc1C#N
Reactant: Ic1ccncc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccnc21
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
tert-Butyllithium (1.5 M solution in pentane, 2.15 mL) was diluted with anhydrous THF (10 mL) at −100° C. under an atmosphere of argon. To this was added dropwise a solution of 4-iodopyridine (330 mg, 1.773 mmol) in anhydrous THF (8 ml,), the mixture was stirred at −100° C. for 5 min and then a solution of N-[(1E)-(3-bromophenyl)(2-cyanopyridin-3-yl)methylene]-2-methylpropane-2-sulfinamide (Example 2, 629 mg, 1.612 mmol) in THF (10 mL) was added dropwise while maintaining the temperature at or below −100° C. The mixture was stirred for 1.5 h during which time it was allowed to warm up to −75° C. The reaction was quenched by the addition of water and the mixture was diluted with ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate and brine, then dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (10 mL) and treated with 2 M hydrochloric acid in diethyl ether overnight at room temperature. The solvents were evaporated and the residue was taken up with saturated aqueous hydrogen carbonate and dichloromethane. The phases were separated, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. Purification by column chromatography using a gradient of increasing concentration of 2 M methanolic ammonia in dichloromethane (from 0 to 5%) gave 406 mg (69% yield) of the title compound. 1H NMR (CDCl3) δ 8.67 (dd, 1H), 8.53 (m, 2H), 7.90 (dd, 1H), 7.41 (m, 3H), 7.23 (m, 3H), 7.18 (m, 1H); MS (ESI) m/z 365, 367 [M+1]+.
Reaction SMILES: C(OC([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)NCCO2
Reaction time: 5 h

Procedure:
To a solution of dichloromethane (10 mL) containing N-(tertbutoxycarbonyl)-2,3-dihydro-benzo[1,4]oxazine (0.438, 1.86 mmol) at 0° C. was added slowly trifluoroacetic acid (1.0 mL, 7.44 mmol). The reaction mixture was stirred at this temperature during 5 h, then the solvent was removed in vaccuo. The crude product was dissolved in EtOAc (15 mL) and washed successively with 10% Na2CO3 solution and water. The organic layer was dried over MgSO4 and the solvent was removed under reduce pressure. The title compound was obtained pure as brown oil (0.245 g, 98%). Rf=0.31 (petrol/ether 5/5); LCMS m/z 136 ([M+1]+); 1H NMR (300 MHz, CDCl3): δ 3.43 (4H, m); 3.54 (1H, s); 4.27 (4H, m); 6.60-6.82 (4H, m); 13C NMR (75 MHz, CDCl3) δ 43.4; 67.7; 118.1; 119.2; 121.3; 123.7; 136.1; 146.6. IR (film): 3375; 1498; 741 cm−1.
Reaction SMILES: [P:1]([O-:49])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46])([O:3][CH2:4][CH:5]([O:26]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]>C(O)C.C(O)(=O)C.[Pd]>[P:1]([O-:49])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N+:45]([CH3:48])([CH3:47])[CH3:46])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCCCC[N+](C)(C)C)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCCCC[N+](C)(C)C
Yield: 88.8 %

Procedure:
1.31 g (1.8 mmole) of the compound of Example 4 was dissolved in a mixture of 100 ml of ethanol and 50 ml of 70% acetic acid. Then, 0.6 g of 10% Pd-C was added thereto and catalytic reduction was carried out at room temperature. 19 hours later, the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was solidified by acetone to give 994 mg (yield: 87.2%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6]Br.[C:17]([NH:24][C@H:25]([C:36]([OH:38])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[CH3:22][C:20]([CH3:23])([O:19][C:17]([NH:24][CH:25]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:36]([O:38][CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1)=[O:37])=[O:18])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Following the method of Example 1, 3,5-bistrifluoromethylbenzyl bromide (4.9 g) and N α BOC-L-tryptophan (5 g) gave the title compound after recrystallisation from ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>C(Cl)Cl>[CH3:30][S:31]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)=[N:15][CH:16]=3)[S:21][C:22]=2[CH:28]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(NS(C)(=O)=O)cc4s3)cn2)CC1
Yield: 48.8 %

Procedure:
To 4-[5-(6-amino-benzothiazol-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (12.7 mg, 0.031 mmol) in DCM (1 mL) was added methanesulfonyl chloride (3 μL, 0.034 mmol) followed by pyridine (3 μL, 0.034 mmol). The r.m. was stirred o.n. at r.t. The crude mixture was purified by flash column chromatography (heptane:ethyl acetate; 50:50 to 40:60), to give intermediate tert-butyl 4-(5-{6-[(methylsulfonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)piperazine-1-carboxylate (7.4 mg) as a solid. MS m/z (M+H) 490, (M−H) 488. This intermediate was dissolved in DCM (1 mL) and TFA (300 μL) was added. The reaction mixture was thereafter stirred for three hours at r.t. The solvent was removed in a stream of nitrogen and the residue was dissolved in DMF (400 μL) and purified by prep. HPLC, to give the title compound (3 mg) as a white solid. 1H NMR δ 8.71 (d, 1 H) 8.09 (dd, 1 H) 7.72-7.86 (m, 2 H) 7.27 (dd, 1 H) 6.88 (d, 1 H) 3.63-3.77 (m, 4 H) 2.95-3.08 (m, 4 H) 2.90 (s, 3 H); MS m/z M+H 390, M−H 388.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH:20]([CH3:23])[CH:21]=[CH2:22]>C(O)C>[CH2:23]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH2:1])[CH:11]=[CH:10]2)/[CH:20]=[CH:21]/[CH3:22]
Reactant: C=CC(C)Cl
Reactant: Nc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C/C=C/COc1cccc2ccc(N)nc12
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A 250 mL round bottom flask was charged with 2.00 g (12.5 mmol) of 2-amino-8-hydroxyquinoline, 3.46 g (25.0 mmol), of K2CO3 and 63 mL of anhydr ethanol. Following the dissolution of 2-amino-8-hydroxyquinoline, 1.51 mL of 3-chloro-1-butene (15.0 mmol) was added in one portion, and the mixture was heated to 65° C. in an oil bath. After 48 h, the solvent was evaporated and the residue dissolved in EtOAc and washed with H2O. The combined aqueous layers were back-extracted with EtOAc. The organic layers were then pooled, dried, and filtered. The residue was then purified by column chromatography (SiO2; EtOAc/hexanes with 0.1% Et3N). The resultant material was then re-crystallized from Et2O to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82 (m, 1H), 7.16 (m, 1H), 7.00 (m, 2H), 6.73 (m, 1H), 6.39 (m, 2H), 5.67–5.98 (m, 2H), 4.44–4.67 (m, 2H), 1.74 (m, 3H); MS (DCI/NH3) m/z 215 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])/[C:25](/[C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:26]\[O:27][CH3:28])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[NH2:8].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37].Cl>CN(C)C=O.C(OCC)(=O)C>[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])/[C:25](/[C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:26]\[O:27][CH3:28])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([O:20][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:19])(=[O:9])[NH2:8]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: CC(=O)OC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.42 h

Procedure:
Potassium carbonate (760 mg, 5.5 mmole) was added to a solution of (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (4.57 g, 11 mmole) in N,N-dimethylformamide (25 ml) and the mixture was stirred at ca 20° for 25 minutes. 1-Bromoethyl acetate (1.8 g, 11 mmole) in N,N-dimethylformamide (5 ml) was added to the above solution and the reaction mixture was stirred for 40 minutes at ca 20°. The reaction mixture was worked up by pouring it into excess 2 N hydrochloric acid, followed by extraction with ethyl acetate (3 times). The combined organic extracts were washed with 2 N hydrochloric acid and saturated sodium bicarbonate solution, dried (magnesium sulphate) and evaporated in vacuo to yield a foam which was dissolved in ethyl acetate and precipitated from ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2([C:13]([CH3:16])([CH3:15])[CH3:14])C[O:11]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([OH:11])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C1(C=Cc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Solvent: CCO
Product: CC(C)(C)C(O)(C=Cc1ccc(Cl)cc1)n1cncn1
Yield: 80.9 %

Procedure:
A solution of 17.75 g (0.075 mol) of 2-(4-chlorophenyl-ethenyl)-2-tert.-butyl-oxirane and 6.9 g (0.1 mol) of 1,2,4-triazole in 30 ml of ethanol was heated in a bomb tube at 150° C. for 20 hours. The reaction mixture was thereafter concentrated, and the crystalline residue was stirred with ether. The solid material was then filtered off under suction and was recrystallized from acetonitrile. 17.7 g (77% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl)-1-penten-3-ol of melting point 139°-141° C. were obtained.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCOCC5)cc4)cc23)CC1
Yield: 3.6 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), morpholine (18 uL, 0.206 mmol) and NaBH(OAc)3 (290 mg, 1.37 mmol) were reacted to give the title compound (2.1 mg, 13%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH3:26])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccccc1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:31]1([S:37]([C:40]2[CH:41]=[C:42]([S:45](Cl)(=[O:47])=[O:46])[S:43][CH:44]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:45]([C:42]3[S:43][CH:44]=[C:40]([S:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:39])=[O:38])[CH:41]=3)(=[O:46])=[O:47])[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccccc2)cs1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccc(NS(=O)(=O)c4cc(S(=O)(=O)c5ccccc5)cs4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.7 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.200 mmol) (from Example 4 supra), Et3N (28 μL , 0.201 mmol), and 4-benzenesulfonylthiophene-2-sulfonyl chloride (64.6 mg, 0.200 mmol) (Lancaster) in 7 mL of 1,2-dimethoxyethane (Fisher Scientific) was heated at reflux for 1 h. The reaction mixture was allowed to cool and then stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 45% ethyl acetate-hexanes elution) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]-4-(phenylsulfonyl)-2-thiophenesulfonamide (yield: 42 mg, 36%) as a yellow solid (mp 132-134° C.) (solid to gel).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH3:37][C:38]1([C:41](O)=[O:42])[CH2:40][CH2:39]1>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:41]([C:38]2([CH3:37])[CH2:40][CH2:39]2)=[O:42])[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: CC1(C(=O)O)CC1
Product: CC1(C(=O)N2CC(CC#N)(n3cc(-c4cnn5c(-c6cccc(NC(=O)NCC(F)(F)F)c6)cnc5c4)cn3)C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and 1-methylcyclopropanecarboxylic acid. LCMS (M+H)+: m/z=578.2
Reaction SMILES: [NH3:1].O.[CH2:3]([CH:7]1[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]1)[CH:4]([CH3:6])[CH3:5]>C(OC)(C)(C)C>[C:9]([CH2:8][CH:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:13][C:12]([OH:11])=[O:14])(=[O:10])[NH2:1]
Reactant: CC(C)CC1CC(=O)OC(=O)C1
Reactant: N
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)CC(CC(N)=O)CC(=O)O
Temperature: 15 °C

Procedure:
Aqueous ammonia (308 g of 28% ammonium hydroxide, 5.06 mol), water (431 g), and methyl tert-butyl ether (200 g) are combined and cooled to 15° C. 3-Isobutylglutaric acid anhydride is added and the reaction mixture is allowed to warm to 50° to 60° C. The reaction mixture is cooled to 20°-25° C. The solvent is evaporated and the pH of the solution is adjusted to 1.0 with concentrated hydrochloric acid. Water (200 mL) is added and the mixture is filtered. The solid is washed with water (200 mL). The solid is dried under reduced pressure to give 408 g of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid as an off-white solid. (±)-3-(Carbamoylmethyl)-5-methylhexanoic acid has a melting point in the range of about 107.5° to about 108.5° C. 1H-NMR (DMSO-d6, 200 MHz): δ 0.84 (d, 6H, J=6.5 Hz), 1.07-1.17 (m, 2H), 1.50-1.72 (m, 1H), 1.98-2.25 (m, 5H), 6.75 (s, 1H), 7.30 (s, 1H), 11.6 (s, 1H). IR (KBr): 592.0, 655.7, 700.0, 1010.5, 1133.9, 1214.9, 1241.9, 1278.6, 1294.0, 1427.1, 1461.8, 1585.2, 1668.1, 1700.9, 2514.7, 2622.7, 2962.1, 3220.5, 3367.1 cm-1.
Reaction SMILES: [Cl-].[Cl:2][CH:3]=[N+:4]([CH3:6])[CH3:5].C([Si](C(C)C)(C(C)C)[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(C)C>C(Cl)Cl>[Cl-:2].[CH3:5][N+:4]([CH3:6])=[CH:3][C:13]1[CH:14]=[CH:15][NH:11][CH:12]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Product: C[N+](C)=Cc1cc[nH]c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 127.8 %

Procedure:
10.60 g of (chloromethylene)dimethylammonium chloride and 6.25 g of N-(triisopropylsilyl)-pyrrole are suspended in 200 ml of CH2Cl2 under nitrogen at 0-5° C. The suspension is warmed to 60° C. and stirred for 30 minutes. Afterwards the mixture is cooled to ambient temperature. The suspension is filtered and washed with diethylether to give 5.67 g of the title compound as grey solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:6]2[N:7]=[C:8]([CH3:11])[S:9][C:10]=2[C:2]([N:1]=[C:15]=[O:14])=[C:3]([F:13])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc2c(Cl)cc(F)c(N)c2s1
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)cc(F)c(N=C=O)c2s1

Procedure:
A solution of 3.2 g (15 mmol) of 7-amino-4-chloro-6-fluoro-2-methylbenzothiazole and 15 g (76 mmol) of diphosgene in 150 ml of toluene was refluxed for 6 hours. The crude product obtained after evaporation was converted directly into active ingredient I.15.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH3:34][S@:26](=[N:25][C:23]([C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1)=[O:24])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)cc1
Yield: 44.1 %

Procedure:
In a manner similar to that described in Example 449, tert-butyl 4-ethynylphenylcarbamate (0.096 g, 0.443 mmol) and 5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (63 mg, 0.13 mmol, 45%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:22]3[CH:23]=[C:24]4[N:31]([CH3:32])[CH2:30][CH2:29][N:25]4[C:26](=[O:28])[N:27]=3)=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.83 mg, 0.246 mmol), 2-((5-fluoropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (45.6 mg, 0.246 mmol).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:42])[CH2:21][N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:23]2=[O:41])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:42])[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:23]2=[O:41])[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)C(=O)C1c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(CN1CCNC(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
The compound from Example 101D (0.24 g, 0.42 mmol) was dissolved in methanol and treated with 4 N HCl in dioxane at ambient temperature for 2 hours. The reaction mixture was concentrated and then partitioned in 1 N NaOH/methylene chloride. The organic layer was dried over MgSO4, concentrated in vacuo and chromatographed, eluting with 5% MeOH/methylene chloride to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.15-7.48 (m, 15H), 4.30-4.44 (m, 3H), 3.91-4.27 (m, 2H), 3.33-3.55 (m, 4H), 2.80-3.07 (m, 4H), 2.23-2.34 (m, 4H); MS (ESI+) m/z 469 (M+H)+.