Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[NH2:16].C(Cl)Cl.[K+].[Br-]>>[CH3:23][O:22][C:18]1[CH:17]=[C:15]([NH:16][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([Cl:10])[N:6]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CNc1nc(Cl)nc(Cl)n1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Cl)nc(Nc2cc(OC)c(OC)c(OC)c2)n1
Yield: 65 %

Procedure:
The title compound was synthesized from 2-methylamino-4,6-dichloro-1,3,5-triazine and 3,4,5-trimethoxyaniline using a similar procedure to the one used in 2. Yield: 65%; Tm 237° C.; FTIR (CH2Cl2/KBr) 3270, 3134, 3051, 2964, 2940, 2842, 2831, 1658, 1631, 1612, 1588, 1567, 1535, 1502, 1453, 1422, 1390, 1351, 1297, 1264, 1230, 1201, 1189, 1172, 1128, 1082, 1057, 1034, 997, 978, 924, 882, 830, 809, 735, 704, 679 cm−1; 1H NMR (300 MHz, DMSO-d6, 298K) δ 9.97, 9.77 (s, s, 1H), 8.09, 7.91 (s, s, 1H), 7.21, 7.09 (s, s, 2H), 3.74 (s, 6H), 3.61 (s, 3H), 2.86, 2.80 (d, d, 3J=4.6 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 167.4, 165.8, 165.6, 163.3, 162.9, 152.5, 135.0, 134.8, 133.2, 133.0, 98.2, 97.6, 60.0, 55.8, 55.5, 27.4, 27.2 ppm; HRMS (EI) calcd. for C13H16ClN5O3 (m/e): 325.0942. found: 325.0934.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:1]=[C:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:11]=2)[CH:14]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc2nc(-c3ccccc3)cn2c1
Yield: 80.8 %

Procedure:
Dissolving 5.8 g (29 mmol) of phenacyl bromide and 5.0 g (29 mmol) of 2-amino-5-bromopyridine into 50 milliliter of ethanol, adding 3.6 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 6.4 g of 6-bromo-2-phenyl-imidazo [1,2-a] pyridine (yield: 81%).
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:13])(=O)[CH2:9][CH2:10][CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27](=[N:57]O)[C:28]1[CH:56]=[CH:55][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][C:46]3[CH:54]=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=3)[CH2:38][CH2:37]2)=[CH:30][CH:29]=1>O.C(OCC)(=O)C>[NH2:57][C:27](=[N:26][O:13][CH2:8][CH2:9][CH2:10][CH3:11])[C:28]1[CH:56]=[CH:55][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][C:46]3[CH:47]=[CH:48][C:49]([C:50]([NH2:52])=[O:51])=[CH:53][CH:54]=3)[CH2:38][CH2:37]2)=[CH:30][CH:29]=1
Reactant: CCCC(=O)O
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To an N-methyl-2-pyrrolidone (10 mL) solution of 0.42 g of butyric acid was added 0.76 g of 1,1′-carbonyldiimidazole at room temperature, which was then stirred at the same temperature for one hour. An N-methyl-2-pyrrolidone (10 mL) solution of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added to the mixture at room temperature, which was then stirred at the same temperature for 14 hours. The reaction mixture was added to a mixture of ethyl acetate and water. The precipitate was collected by filtration and washed with ethyl acetate to provide 1.10 g of 4-{3-[4-(3-{4-[amino(n-butyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(butyryl)oxime as white solid form.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1B(O)O>>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=4[N:7]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: OB(O)c1cc2ccccc2[nH]1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Product: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(C)(=O)=O

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 194. NMR: (400 MHz, DMSO) 2.83 (s, 3H), 3.02 (s, 3H), 3.85 (t, J=4.7, 4H), 3.99 (t, J=4.7, 4H), 4.64 (s, 2H), 7.19 (t, J=7.7, 1H), 7.43 (m, 2H), 7.51 (m, 2H), 8.12 (d, J=7.3, 1 H), 11.20 (s br, 1H) MS: (ESI+): [M+H]+ 458.01
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22](=[O:33])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH2:24].F[C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1>>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH3:25].[CH3:20][O:21][C:22](=[O:33])[C@@H:23]([NH:24][C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: CCC(=O)OC
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(C#N)cc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-(4-Hydroxy-phenyl)-(2S)-[4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (664 mg) was prepared starting from 4′-trifluoromethyl-biphenyl-4-carboxylic acid (532 mg, 2.0 mmol) and tyrosine methyl ester (462 mg, 2.0 mmol) according to general procedure A. The above compound (443 mg, 1.0 mmol) was treated with 1-fluoro-4-cyanobenzene (181 mg, 1.5 mmol) following general procedure B to give 3-[4-(4-cyano-phenoxy)-phenyl]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (360 mg). The ester was hydrolyzed following general procedure C to give the title compound (345 mg)
Reaction SMILES: Br[C:2]1[C:8](=[O:9])[C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1[C:31](=[O:32])C(N2CCNCC2)=CC=CC=1.ClC1C=CC(CBr)=CC=1>>[CH3:31][O:32][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[C:8](=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=c1c(Br)ccccc1N1CCNCC1
Reactant: O=c1c(Br)ccccc1N1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Clc1ccc(CBr)cc1
Product: COc1cccc(CN2CCN(c3cccccc3=O)CC2)c1

Procedure:
7-bromo-2-[4-(4-chlorobenzyl)-1-piperazinyl]-2,4,6-cycloheptatriene-1-one, from 7-bromo-2-(1-piperazinyl)-2,4,6-cycloheptatriene-1-one of example 2b and 4-chlorobenzyl bromide.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8](I)[C:7]([C:22]#[N:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2].[CH3:25][C:26]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([CH:25]=[CH2:26])[C:7]([C:22]#[N:23])=[C:6]([Cl:24])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)c1cc(Cl)c(C#N)c(I)c1OCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1c(C#N)c(Cl)cc(C(C)=O)c1OCCNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-iodophenoxy)ethyl]carbamate (3.3 g, 7.1 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.81 mL, 10.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.3 g, 0.4 mmol) and potassium carbonate (2.9 g, 21 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was degassed with nitrogen. The resulting mixture was heated at 80° C. for 1 h. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The product was purified by FCC on silica gel using ethyl acetate in hexane (0-40%) to give the desired compound tert-butyl [2-(6-acetyl-4-chloro-3-cyano-2-vinylphenoxy)ethyl]carbamate as a crystalline solid (2.2 g. 85%). LCMS calculated for C18H21ClIN2O4Na (M+Na)+: m/z=387.1; found: 387.0.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:21](=[O:22])[C:4]=2[CH:3]=1)[CH2:18][CH2:17][N:16](C#N)[CH2:15][CH2:14]3.C(O)(=O)C.[BrH:29]>Cl.O.CCOCC>[BrH:29].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:21](=[O:22])[C:4]=2[CH:3]=1)[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3
Reactant: N#CN1CCC2(CC1)C(=O)c1cc(Cl)ccc1Oc1ccccc12
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: O=C1c2cc(Cl)ccc2Oc2ccccc2C12CCNCC2
Temperature: 25 °C

Procedure:
A homogeneous solution of 1.8 g of 2-chloro-1'-cyano-10,11-dihydro-11-oxospiro[dibenz(b,f)oxepin-10,4'-piperidine], Example 4, in 20 ml of 3 N hydrochloric acid and 10 ml of glacial acetic acid is stirred at 110°-120° C. for 16 hours and then the solution is permitted to cool to ambient temperature. Thereafter, the solution is diluted with 50 ml of water and then is rotary evaporated at 80° C. until 50 ml of water is removed and the dilution and evaporation process is repeated. The residue is diluted with 200 ml of water and the diluted solution is successively cooled in an ice bath, basified to pH 9 with a small amount of 58% ammonium hydroxide and extracted thrice with 80 ml portions of ether. The combined ether extracts are sequentially washed twice with two 80 ml portions of water and one 40 ml portion of saturated sodium chloride and then dried over magnesium sulfate and finally evaporated to dryness leaving an oil. The oil is dissolved in ether where it is converted to its hydrobromic acid salt. The salt is recrystallized from acetone to provide crystals of 2-chloro-10,11-dihydro-11-oxospiro[dibenz(b,f)oxepin-10,4'-piperidine]hydrobromide which lose their regular shape upon heating above 125° C. and the resulting glass melts at 223°-225° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44])[N:11]=[C:12]3[C:21]4[C:16](=[C:17]([O:30]CC5C=CC=CC=5)[CH:18]=[CH:19][C:20]=4[O:22]CC4C=CC=CC=4)[C:15](=[O:38])[C:14]=1[C:13]=23.[ClH:45]>C(O)(=O)C.CC(O)C.[OH-].[OH-].[Pd+2]>[ClH:45].[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44])[N:11]=[C:12]3[C:21]4[C:16](=[C:17]([OH:30])[CH:18]=[CH:19][C:20]=4[OH:22])[C:15](=[O:38])[C:14]=1[C:13]=23
Reactant: NCCCNc1ccc2c3c(nn2CCNCCO)-c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2C(=O)c13
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: NCCCNc1ccc2c3c(nn2CCNCCO)-c2c(O)ccc(O)c2C(=O)c13
Yield: 82 %

Procedure:
A mixture of 9.5 g (0.016 mol) of 5-[(3-aminopropyl)amino]-2-[2-(2-hydroxyethyl)amino]ethyl]-7,10-bis(phenylmethoxy)anthra[1,9-cd[pyrazol-6(2H)-one (3) in 300 ml of acetic acid was hydrogenated over 1.7 g of 20% palladium hydroxide on carbon at atmospheric pressure and at room temperature for two hours, filtered through celite, and concentrated under vacuum. The residue was dissolved in boiling methanol. The hot solution was treated with an excess (about 0.05 mol) of hydrogen chloride in 2-propanol, and chilled overnight. The red-orange precipitate was collected, washed with 2-propanol, dried at 65° C. under vacuum for 48 hours, and allowed to equilibrate in the air overnight to afford 6.4 g (82%) of 4, containing 0.6 mole of water, mp 267°-272° C. (dec) with prior sintering.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C(OCC)(=O)C.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>[F:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(Cc2cccc(F)c2)c(F)c1
Temperature: 130 °C
Yield: 66 %

Procedure:
Methyl 4-(bromomethyl)-3-fluorobenzoate (0.285 g; 1.15 mmol) was suspended in a mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) and 3-fluorophenylboronic acid (0.183 g; 1.27 mmol), tetrakis(triphenylphosphine)palladium(0) (0.067 g; 0.0058 mmol) and sodium carbonate (0.246 g; 2.31 mmol) were successively added. The resulting suspension was heated at 130° C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane) to give 0.199 g (66%) of methyl 3-fluoro-4-(3-fluorobenzyl)benzoate as an oily residue which was directly used in the next step.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9]>C(O)C.C(N)CC>[OH:1][CH:2]([CH2:3][NH:10][CH2:8][CH2:7][CH3:6])[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Solvent: CCCN
Solvent: CCO
Product: CCCNCC(O)COc1ccccc1C(=O)Nc1cccc2[nH]ccc12
Yield: 151.6 %

Procedure:
3.1 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl) benzamide prepared as in example 4 is heated for 2 hours to reflux in 60 cm3 of ethanol and 8.5 cm3 of n-propylamine. The solvent are eliminated under reduced pressure at 50° C., the residue is chromatography on silica (eluent:chloroform-methanol 7-3) to obtain 2.8 g of 2-[2-hydroxy-3-(propylamino)-propoxy]-N-(1H-indol-4-yl) benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1.O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:20](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A stirred slurry of 21.1 g (0.1 mole) of 5-chloro-2-oxindole-1-carboxamide and 26.9 g (0.22 mole) of 4-(N,N-dimethylamino)pyridine in 200 ml of N,N-dimethylformamide was cooled to ice-bath temperature, and then a solution of 16.1 g (0.11 mole) of 2-thenoyl chloride in 50 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for ca. 30 minutes, and then the reaction mixture was poured into a mixture of 1 liter of water and 75 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath, and then the solid was collected by filtration. The solid was washed with water and then recrystallized from 1800 ml of acetic acid, to give 26.6 g of the title compound as fluffy, yellow crystals, m.p. 230° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:20])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-hydroxy pyrrolidine (10 g, 40.81 mmol) in DMF (60 mL) at 0° C. was added NaH (2.9 g, 122.4 mmol) and the resultant mixture was allowed to stir at the same temperature for 30 min. To this mixture was added MeI (5.08 mL, 81.63 mmol) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was poured onto ice-cold water (200 mL) and extracted with EtOAc (250 mL). The organic layer was washed with water (8×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-methoxy pyrrolidine (9 g) which was used for the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([OH:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1.Cl.[CH3:20][O:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[S:1]1[CH:5]=[C:4]([C:6]2[N:15]=[C:14]([C:16]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[O:21][CH3:20])[CH2:27]3)=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[N:3]=[CH:2]1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2cscn2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cscn3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-thiazolyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 81 (15% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.86 and 3.12 (2t, 2H), 3.54 and 4.16 (2t, 2H), 3.81-3.90 (m, 6H), 4.43 and 5.05 (2s, 2H), 6.51 and 6.90 (2d, 1H), 6.71 and 7.01 (2d, 1H), 7.63-7.68 (m, 1H), 7.94-8.04 (m, 2H), 8.28-8.31 (m, 1H), 8.53-8.57 (2s, 1H), 9.02-9.03 (2s, 1H); MS (ESI) m/z 433 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[O:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:14]=3[CH2:13][CH2:12][C:11]=2[CH:24]=1.[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:26]1([CH2:29][N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[O:16][C:15]4[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:4][CH2:3][CH:2]([CH3:25])[CH3:1])[CH2:28][CH2:27]1
Reactant: O=CC1CC1
Reactant: CC(C)CCNCc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CCN(Cc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2)CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of amine of example 1 (30 mg, 0.09 mmol) in MeOH-AcOH 5% (0.5 mL) add cyclopropanecarboxaldehyde (0.18 mmol). Stir the mixture at room temperature overnight. Add NaBH3CN and stir the mixture at room temperature for about two hours. Add more aldehyde (1.5 mmol) and stir overnight. Purify by SCX ion-exchange chromatography to obtain the title compound (22 mg). 1H-NMR (CD3OD, 300 MHz): 7.72-7.69 (m, 2H), 7.21-7.09 (m, 4H), 3.64 (s, 2H), 3.14 (bs, 4H), 2.61-2.56 (m, 2H), 2.37 (d, 2H, J=6.5 Hz), 1.60-1.37 (m, 4H), 0.87 (d, 6H, J=6.7 Hz), 0.55-0.49 (m, 2H), 0.13-0.08 (m, 2H). Electrospray MS M+1 ion=393.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:32][CH2:31][O:30][C:29]3=[O:33])[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:32][CH2:31][O:30][C:29]3=[O:33])[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34]
Reactant: CC1(C)CC(c2cccc(N3CCOC3=O)c2)Nc2c(C(=O)O)cc(Cl)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOC3=O)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a suspension of methanesulfonamide (665 mg, 7 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (280 mg, 7 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A64. A solution of 6-chloro-4,4-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (400 mg, 1 mmol) and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B64. Solution B64 was added to Solution A64 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{6-chloro-4,4-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-methanesulfonamide (37 mg, 7%) as a white solid: MS (ESI) M+1=478.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[N:28])[C:17]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:32](OC)([N:34](C)C)[CH3:33].[NH2:39]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[N:28])[C:17]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:39][NH:34][C:32]([CH3:33])=[C:10]2[N:9]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NN
Reactant: COCCOCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2
Product: COCCOCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-(2-(2-methoxyethoxy)ethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVn) was prepared by reacting 0.00067 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-(2-methoxyethoxy)ethoxy)-2H-1,4-benzodiazepin-2-thione (IIn) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=452.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(CO)CCC1NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(NCc3ccccc3)C(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Benzylamino-3-methyl-cyclohexyl)-methanol (0.1 g, 3.00 mmol) in DCM (30 mL) and pyridine (3 mL) is treated with TsCl (0.86 g, 4.50 mmol) and the resulting mixture is stirred at RT overnight. The reaction mixture is partitioned between DCM and water and the organic portion is separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane:EtOAc (1:2 increasing to 1:4) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2H, d), 7.50 (2H, d), 7.30 (4H, m), 7.20 (1H, m), 3.80 (2H, d), 3.63 (2H, q), 2.41 (4H, m), 2.01 (1H, m), 1.72 (2H, m), 1.58 (1H, m), 1.49 (2H, m), 1.20 (1H, m), 1.02 (1H, m), 0.85 (1H, m), 0.81 (3H, d).