Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(OC(=O)C)C.C(O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1c(C)cccc1N
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Dissolve 2-Amino-6-methyl-benzoic acid (3.00 g, 19.8 mmol) in ethylacetate (100 mL) and ethanol (100 mL) and add (trimethylsilyl) diazomethane (19.8 mL, 39.7 mmol, 2M in hexane) at room temperature and stir the solution for 1 h 30 min. Remove the solvent under reduced pressure to afford the title compound (3.30 g, quantitative). 1H NMR (CDCl3, 300 MHz) δ 2.43 (s, 3H), 3.89 (s, 3H), 5.11 (brs, 2H), 6.52 (m, 2H), 7.08 (t, J=7.7 Hz, 1H). MS (ES+): 166 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:32])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.O>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH:23]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[OH:31])=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:32])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(=O)c2ccc(F)cc2)cn1)N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(C(O)c2ccc(F)cc2)cn1)N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-fluorobenzoyl)-2-pyridinyl]urea (20 mg) was dissolved in methanol and sodium borohydride (appr. 20 mg) was added to the reaction mixture in small portions. The reaction mixture was stirred for about 3 h at ambient temperature. The reaction was monitored by TLC. The reaction mixture was diluted with water, acidified with 1N HCl and extracted into methylene chloride. Organic extract low as washed with water and bine, dried over magnesium sulfate and concentrated. Purification by column chromatography on silica (EtOAc/hexane) gave 12 mg of pure product.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]([C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([OH:14])=[O:13]>O.CC(C)=O>[CH2:11]([N:18]1[CH2:19][CH2:20][C:15]([C:12]([OH:14])=[O:13])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
106 ml of a 30% NAOH solution is added to a suspension of 100 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 600 ml of water, then the thus obtained solution is cooled to 5° C., a solution of 47.6 g of bromide benzyl in 100 ml of acetone is added dropwise and left under stirring for 1 hour while the temperature being allowed to rise to RT. The acetone is evaporated under vacuum, and the pH of the remaining aqueous phase is brought to 9.5 by adding concentrated aqueous solution of HCl, then the pH is adjusted to 8.5 by adding a 2N HCl solution. The precipitate formed is wrung and washed with water and then with acetone to give 70 g of the expected compound, M.p.=286° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.Br[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[N:26]1([C:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:10]3[N:9]=[C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:33]5[N:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH2:3]4)[CH:16]=[CH:15][C:11]=3[C:12]([NH2:14])=[O:13])=[CH:23][CH:22]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: Brc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(N2CCC[C@@H](Nc3ncccn3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A mixture of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (50 mg, 0.118 mmol), 2-bromopyrimidine (22.47 mg, 0.141 mmol), and DIEA (0.041 mL, 0.236 mmol) in THF (1 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water, 10% LiCl, and concentrated. The residue was purified by prep-HPLC and the product containing fractions were collected, basified with 1N NaOH, extracted with CH2Cl2, washed with water, and concentrated to give 18 mg of (R)-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(3-(pyrimidin-2-ylamino)piperidin-1-yl)nicotinamide as a light yellow solid. LCMS: (M+H)+=503.23. 1H NMR (500 MHz, CDCl3) δ ppm 11.19 (1H, s), 8.27 (2H, d, J=4.58 Hz), 7.68 (2H, d, J=8.71 Hz), 7.51 (1H, d, J=8.71 Hz), 7.27 (2H, d, J=8.71 Hz), 6.56 (1H, t, J=4.81 Hz), 6.12 (1H, d, J=9.16 Hz), 5.57 (2H, br. s.), 5.26 (1H, d, J=7.79 Hz), 4.20 (1H, dd, J=12.83, 3.21 Hz), 4.09 (1H, dt, J=7.79, 3.89 Hz), 3.89-3.98 (1H, m), 3.49-3.83 (8H, m), 3.42-3.48 (1H, m), 3.39 (1H, dd, J=12.83, 7.79 Hz), 2.04-2.13 (2H, m), 1.69-1.92 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:37])[CH2:28][NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(Cl)=[O:46].CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[O:37][C:45](=[O:46])[N:29]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:28]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CN(Cc5ccccc5)C(=O)O4)cc3)cc2)CC1
Temperature: 0 °C

Procedure:
1-{4′-[4-(2-Benzylamino-1-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.190 g, 0.38 mmol) was dissolved in toluene (4 mL) then placed under N2 atmosphere at 0° C. Triethylamine (0.159 mL, 1.14 mmol) and phosgene (1.9M in toluene, 0.201 mL, 0.38 mmol) were added and the reaction stirred at 0° C. After two hours an additional portion of each of triethylamine (0.160 mL) and phosgene (0.200 mL) were added and the reaction stirred an additional 20 minutes. The reaction was submitted to standard workup procedures and silica gel chromatography (0-40% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C:11]([NH2:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22](N)=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CCOCC>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C:11]([NH:14][C:22]3[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(NC2=NN(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 29.7 %

Procedure:
A mixture of 1-(3-trifluoromethylphenyl)-4,5-dihydro-1H-pyrazol-3-amine (0.23 g), 4-methoxyaniline (0.37 g) and p-toluenesulphonic acid (0.17 g) was heated in an oil bath at 140° under nitrogen for 15 minutes. The reaction was cooled, dilute hydrochloric acid and ether added and the organic phase separated, dried over sodium sulphate, filtered and evaporated to leave a yellow solid, which on trituration with pentane gave the colourless title compound (0.1 g) m.p. 127°-8°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.Cl.[NH+]1C=CC=CC=1>>[F:22][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[C:9]([C:12]#[N:13])[C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=3)[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1F
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(-c2ccc(O)c(F)c2)cc2ccc(O)cc12

Procedure:
The title compound was prepared by reacting 7-hydroxy-3-(3-fluoro-4-methoxyphenyl)-1-naphthonitrile (0.12 g, 0.41 mmol) with pyridinium HCl (3 g) according to method B to yield 0.085 g (74%) of a white solid: mp 265-269° C.; 1H NMR (DMSO-d6): δ 7.04-7.09 (1H, m), 7.26 (1H, dd, J=2.31 Hz, J=8.88 Hz), 7.36 (1H, d, J=2.19 Hz), 6.52 (1H, d, J=2.19 Hz), 6.52 (1H, dd, J=1.76 Hz, J=8.40 Hz), 6.71 (1H, dd, J=2.22 Hz, J=12.88 Hz), 8.01 (1H, d, J=8.97 Hz), 8.37 (1H, d, J=1.83 Hz), 8.45 (1H, d, J=1.41 Hz), 10.33 (2H, bs); MS (ESI) m/z278 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13].FC1C=CC=C(F)C=1N.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1c(F)cccc1F
Agent: Nc1c(F)cccc1F
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1c(F)cccc1F
Yield: 37 %

Procedure:
This compound was prepared using 103 mg (0.5 mmol) of 2-[(2,6-difluorophenyl)-hydrazono]malononitrile, which was derived from 2,6-difluoroaniline (108 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 44 mg (37%) of the title compound as an orange solid.
Reaction SMILES: [Si]([O:18][C:19]1[CH:53]=[CH:52][C:22]([O:23][CH2:24][C@@H:25]([OH:51])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:50]=[CH:49][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[S:44][CH:45]=[CH:46][C:47]=4[CH3:48])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:51][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:53][CH:52]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:50]=[CH:49][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[S:44][CH:45]=[CH:46][C:47]=3[CH3:48])=[O:42])[CH2:39][CH2:40]2)=[CH:32][CH:31]=1
Reactant: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 84.7 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(3-methyl-2-thienyl)methanone (0.083 g, 0.111 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.048 g, 0.094 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16].CCN(CC)CC>CO>[OH:16][CH2:15][CH2:17][N:18]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14]
Reactant: NCCO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1CCO
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5-Nitro-isochromen-1-one (3.60 g, 0.0170 mol) was suspended in MeOH (40 mL), ethanolamine (3.11 g, 0.0508 mol) was added and the reaction mixture was stirred at 70° C. for 2 h under an atmosphere of nitrogen. Cooled to room temperature and Et3N (5 mL) was added and the reaction mixture was stirred at room temperature for 2 days. Solid thus formed was filtered out (yellow solid was obtained as the desired product, 0.9 g). Filtrate was concentrated and the residue was dissolved in EtOAc, washed by water and brine, dried over Na2SO4, solvent was removed, to give the product as a yellow solid (1.3 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 91.3 %

Procedure:
A solution of 4-chloro-3-nitro-benzene sulfonamide (5.49 g, 23.2 mmol), cyclohexylamine (4.00 mL, 35.0 mmol), and triethylamine (5.0 mL, 35 mmol) in acetonitrile (75 mL) was refluxed overnight under nitrogen atmosphere. The reaction mixture was concentrated almost to dryness. The residue was diluted in ethyl acetate and washed with 1N hydrochloric acid (1×) and saturated NaHCO3 (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was filtered and washed with hexane to give the product as a yellow solid (6.34 g, 91%). ESI-MS m/e 300.1 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C>CO.C(O)(=O)C>[CH:39]1([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:41][CH2:40]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C3CC3)c(SC)nn12
Temperature: 25 °C

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in methanol (10 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (60 μL), acetic acid (298 μL) and sodium cyanoborohydride (171 mg) were added and the mixture was heated to reflux for 6 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogencarbonate was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (74 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[Cl:7][C:8]1[N:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[C:10](Cl)[N:9]=1>>[Cl:7][C:8]1[N:9]=[C:10]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[C:11]([Cl:15])=[C:12]([Cl:14])[N:13]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: CNS(C)(=O)=O
Product: CN(c1nc(Cl)nc(Cl)c1Cl)S(C)(=O)=O

Procedure:
Following a procedure similar to that of Method 32, the title compound was prepared from N-methylmethanesulfonamide and 2,4,5,6-tetrachloropyrimidine. MS: 290 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:20]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=2)[C:20]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Add acetyl chloride (0.3 mmol) followed by pyridine (0.3 mmol) to a solution of 5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.05 g, 0.1 mmol) in dichloromethane (1 mL). After stirring at room temperature for 24 h remove solvent under vacuum. Chromatograph the product over silica gel using ethyl acetate/hexane (10-40%) to elute. This affords the title compound (0.04 g, 71%) as an oil which foams under vacuum: MS (ES+): 563 (M−H).
Reaction SMILES: [ClH:1].C([NH:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])C1C=CC=CC=1>[Pd]>[ClH:1].[NH2:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(C)(C)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)CC(C)(C)N
Reaction time: 96 h
Yield: 99.1 %

Procedure:
A mixture of 25 g (0.1 mole) of ethyl 3-(N-benzylamino)-3-methylbutyrate hydrochloride and approximately 2 g of 10% Pd-C in 250 ml of dried USP alcohol was hydrogenated under 55 psi H2 for four days. The reaction medium was then filtered and evaporated under reduced pressure to provide 18 g (100%) of an amber oil which gradually crystallized upon standing: mp 82°-83° C.; NMR (CD3OD) δ1.2 (t, J=7, Hz, 3, --CH2CH3) 1.5 (s, 6, two --CH3), 2.8 (s, 2, --CH2 --), 4.2 (q, J=7 Hz, 2, --CH2CH3). Analysis Calculated for C7H16NO2Cl: C, 46.28; H, 8.88; N, 7.71. Found: C, 46.46; H, 8.98; N, 7.90.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.Br[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:33][CH:32]=1)[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:37]([C:34]1[CH:33]=[CH:32][C:31]([CH:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)=[O:7])=[CH:25][CH:26]=2)[CH2:29][CH3:30])=[CH:36][CH:35]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CCC(Br)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(CC)c3ccc(CC(C)C)cc3)cc2)c2ccccn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A mixture of ethyl 4-[1-(4-hydroxybenzoyl)indolizin-3-yl]butyrate (61 mg), 1-bromo-1-(4-isobutylphenyl)propane (53 mg) and potassium carbonate (72 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with n-hexane and ethyl acetate (2:1) to give ethyl 4-[1-[4-[1-(4-isobutylphenyl)propyloxy]benzoyl]indolizin-3-yl]butyrate (80 mg) as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN(C1C=CC=CN=1)C>C(O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(S)cc1
Reactant: COc1ccc2nc(Cl)ccc2c1
Agent: CN(C)c1ccccn1
Solvent: CCO
Product: COc1ccc2nc(Sc3ccc(N)cc3)ccc2c1

Procedure:
2-Chloro-6-methoxyquinoline (52.0 mmoles, 10.0 g), 4-aminothiophenol (52.0 mmoles, 6.5 g) and dimethylaminopyridine (52.0 mmoles, 6.3 g) were stirred for 16 hr in 250 ml ethanol. The reaction was condensed and purified by HPLC over silica gel eluted with 25-30% ethyl acetate/hexane to yield 2-(4-aminophenylthio)-6-methoxyquinoline. 8.5 g, 58% product. Mass spec (FD) 282. Calculated for C16H14N2OS: C, 68.06; H, 5.00, N, 9.92. Found: C, 68.04; H, 4.97; N, 10.02.
Reaction SMILES: [Br:1]Br.[CH2:3]([S:19]([NH:22][C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)Cl>C(O)(=O)C>[CH2:3]([S:19]([NH:22][C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH2:30][Br:1])[CH:26]=[CH:27][CH:28]=1)(=[O:20])=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc(C(=O)CBr)c1

Procedure:
Bromine, 4.72 g (1.52 ml) was added to 25 g (0.059 M) of the product of Step A in 75 ml of glacial acetic acid at 70° C. Decolorization of bromine was instant. The reaction was followed by thin layer chromatography (CH2Cl2, silica gel) until the starting material was practically absent. The solid precipitated on cooling was collected by filtration, recrystallized from hexane to give 23.5 g of product (about 80% based on m-aminoacetophenone): mp 92°-5° C. Mass spectrum showed some dibrominated material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][Br:29])=[CH:19][CH:20]=3)=[N:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nnc(-c3cccc([N+](=O)[O-])c3)s2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(-c2nnc(-c3ccc(CBr)cc3)s2)c1

Procedure:
To a solution of 2-(3'-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole (0.66 g, 2.22 mmol) in CCl4 (75 ml) is added NBS (0.43 g, 2.44 mmol) and refluxed for 12 hours. The mixture is then concentrated and the residue is taken up in chloroform (50 ml) and washed with saturated NaHCO3 (50 ml) and brine (50 ml). The organic layer is dried over MgSO4 and concentrated to yield 2-(3'-nitrophenyl)-5-(p-bromomethylphenyl)-1,3,4-thiadiazole as a tan solid. (0.69 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[S:9]([C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[C:16]4[NH:23][CH:24]=[CH:25][C:15]=4[C:14]=3[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([C:29]([O-:31])=[O:30])C.O.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:26])[S:9]([C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[C:16]4[NH:23][CH:24]=[C:25]([C:29]([OH:31])=[O:30])[C:15]=4[C:14]=3[CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1

Procedure:
This compound is prepared according to synthesis 75 from 412 mg (0.93 mmol) of 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 360 mg (13.95 mmol) of lithium hydroxide monohydrate to give, after acid-basic treatment and precipitation in an acid aqueous phase (pH 5), 200 mg (52%) of 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a pale pink solid.