Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][NH:25][CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[C:42]([F:52])[CH:41]=2)[CH2:36][CH2:35]1)=[O:33].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([C:23]4([O:28][CH3:29])[CH2:27][CH2:26][N:25]([CH2:31][C:32]([N:34]5[CH2:39][CH2:38][N:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:47]=[CH:48][CH:49]=[CH:50][N:51]=7)=[C:42]([F:52])[CH:41]=6)[CH2:36][CH2:35]5)=[O:33])[CH2:24]4)=[O:22])[CH:18]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Reactant: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1(C(=O)Nc2ccc3[nH]nc(-c4ccc(OC(C)C)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)c(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-pyrrolidine-3-carboxylic acid [3-(4-isopropoxy-phenyl)-1H-indazol-5-yl]-amide (8AB) (40 mg, 0.086 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (35 mg, 0.103 mmol, 1.2 equiv) were weighed out in a flask, and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (22 mg, 30 uL, 0.172 mmol, 2 equiv). The reaction content was stirred at room temperature, overnight.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].[CH3:42][S:43]([CH2:46][CH2:47][CH2:48]O)(=[O:45])=[O:44].CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:41][O:40][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:21]=1[O:20][CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:45])=[O:44])[N:28]=[CH:27][N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[C:25]2=[O:39]
Reactant: CS(=O)(=O)CCCO
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCS(C)(=O)=O
Yield: 90.7 %

Procedure:
Triphenylphosphine (8.9 g, 35.2 mmol) was added to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 19.6 mmol), (prepared as described for the starting material in Example 7), in methylene chloride (150 ml). This was followed by the addition of 3-methylsulphonylpropanol (3.5 g, 25.4 mmol) and diethylazodicarboxylate (5.55 ml, 35.2 mmol) in portions. The reaction was complete once the reaction became homogeneous. Silica was added and the volatiles were removed by evaporation. The free flowing powder was placed on the top of a flash chromatography column pre-equilibrated with ethyl acetate (100%). Elution was done using ethyl acetate (100%) followed by methylene chloride/ethyl acetate/methanol (60/35/3). The volatiles were removed by evaporation to give 6-methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7.58 g, 91%) as a white solid.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:9][NH:10][C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14]>>[CH3:9][N:10]1[C:11]2[C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=[CH:18][C:19]=2[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2
Reactant: CNc1ccccc1C(=O)O
Reactant: O=C1CCCCC1Br
Product: Cn1c2c(c3cccc(C(=O)O)c31)CCCC2
Yield: 15 %

Procedure:
Under the conditions of Example 59, 2-bromocyclohexanone is reacted with the methyl ester of N-methylanthranilic acid. After recrystallization from methanol, the methyl ester of 9-methyl-5,6,7,8-tetrahydrocarbazole-1-carboxylic acid is obtained in a 15% yield, m.p. 56° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([C:32]1[CH:33]=[C:34]([C:37](O)=[O:38])[S:35][CH:36]=1)#[N:31]>>[C:30]([C:32]1[CH:33]=[C:34]([C:37]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:38])[S:35][CH:36]=1)#[N:31]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: N#Cc1csc(C(=O)O)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C#N)cs2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 70 mg, 0.18 mmol) and 4-cyanothiophene-2-carboxylic acid (32.9 mg, 0.21 mmol).
Reaction SMILES: Cl.[C:2]([O:6][CH2:7][C@@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:19](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:20][CH:21]([O:23][C:24](=[O:26])[CH3:25])[CH3:22].C(N(CC)CC)C>ClCCl>[C:24]([O:23][CH:21]([O:20][C:19]([NH:9][C@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[CH2:7][O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:27])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC[C@H](N)C(=O)N1CCC[C@H]1C#N
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(C)OC(=O)N[C@@H](COC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Yield: 34.5 %

Procedure:
A solution of (2S)-1-(O′-tert-butylserinyl)pyrrolidine-2-carbonitrile hydrochloride (30 mg, 0.11 mmol; prepared according to Jenkins et al., WO95/15309), α-acetoxyethyl p-nitrophenyl carbonate (32 mg, 0.12 mmol; prepared according to Alexander et al., J. Med. Chem. 31, 318, 1988) and triethylamine (20 mg, 0.20 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60-80° C.; 4:6) yielding a white solid identified as the title compound (14 mg, 0.038 mmol, 35%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH:13]=[CH2:14])C=C>ClCCl>[F:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:11][C:12](=[O:15])[CH:13]=[CH:14][CH2:1][C:4]=2[CH:9]=1
Reactant: C=CCc1cc(F)ccc1NC(=O)C=C
Solvent: ClCCl
Product: O=C1C=CCc2cc(F)ccc2N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round-bottom flask containing the product from Step 2 (4.51 g, 21.9 mmol) was fitted with a stirbar and septa. Dichloromethane (800 mL) and Zhan catalyst I (0.735 g, 1.11 mmol) were added, and the resulting solution was stirred for 18 hours at room temperature. The reaction was then concentrated in vacuo and recrystallized from dichloromethane to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:32](=[O:34])[CH3:33])[CH:14]=[C:13]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](Nc1cc(N)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,4,6-triamine was dissolved in 1 ml of methylene chloride, and 43 μl of triethylamine, 22 μl of acetic anhydride and 1 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water. The solution was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 32 mg of the objective compound as yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[Cl:15])=[CH:9][CH:8]=1.[CH2:28]([NH2:30])[CH3:29].[I-].[K+].[C:33]([OH:45])(=[O:44])[CH2:34][C:35]([CH2:40][C:41]([OH:43])=[O:42])([C:37]([OH:39])=[O:38])[OH:36]>CC(=O)CC.CO.ClCCl.O.C(O)C>[C:33]([OH:45])(=[O:44])[CH2:34][C:35]([CH2:40][C:41]([OH:43])=[O:42])([C:37]([OH:39])=[O:38])[OH:36].[CH2:28]([NH:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[Cl:15])=[CH:9][CH:8]=1)[CH3:29]
Reactant: CCN
Reactant: ClCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CCNCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Combine (E and Z)-1-[4-(4-chlorobutoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene (1.0 g, 2.5 mmol), ethylamine (15 mL, 193 mmol), potassium iodide (0.200 g), ethanol (2 mL), and water (5 mL). Heat to a gentle reflux. After 24 hours, cool to ambient temperature and concentrate in vacuo to obtain a residue. Chromatograph on silica gel eluting with 7% methanol/dichloromethane to obtain a residue. Combine the residue and butanone (6 mL). Add citric acid (0.52 g, 2.7 mmol) dissolved in butanone (4 mL). Allow to slowly evaporate until a solid forms, filter, and dry in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14](N)=[O:15]>O>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:6]
Reactant: NC(N)=O
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Temperature: 200 °C
Yield: 88.8 %

Procedure:
A mixture of 2-amino-5-methoxybenzoic acid (5.00 g, 29.9 mmol) and urea (5.40 g, 90.0 mmol) was heated to 200° C. for 1 hour. The mixture was cooled to room temperature and diluted with H2O (50 mL), the mixture was filtered off and the precipitate was washed with H2O (10 mL), dried in vacuo to give the product (5.10 g, yield 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Product: CCOC(=O)c1cnc2ccccc2c1NC1CCCC1

Procedure:
4-Chloro-quinoline-3-carboxylic acid ethyl ester (125 mg, 0.53 mmol) was treated with cyclopentylamine following general procedure B to afford 4-Cyclopentylamino-quinoline-3-carboxylic acid ethyl ester (110 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (80 mg) following general procedure E. The above ethylamide (0.28 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-cyclopentyl-3-ethyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (15 mg). LCMS: m/z 310 [M+1]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:20]([O:22][Si:23](Cl)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH3:21]>O1CCCC1>[CH3:19][O:18][C:13]([O:17][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])=[C:14]([CH3:16])[CH3:15]
Reactant: COC(=O)C(C)C
Reactant: CCO[Si](Cl)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCO[Si](OCC)(OCC)OC(OC)=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A 3-necked 2-liter flask, equipped with a mechanical stirrer, thermocouple, dry-ice condenser, and a dropping funnel, was charged with tetrahydrofuran (200 mL) and diisopropylamine (70 mL, 0.50 mol) under an argon atmosphere. The mixture was cooled to 0° and n-butyllithium (313 mL, 1.6M in hexane) was added dropwise while the temperature was maintained at about 0°. The mixture was stirred for 30 minutes, followed by dropwise addition of methyl isobutyrate (57.3 mL, 0.50 mol). Stirring was continued at 0° for an additional 30 minutes and triethoxysilyl chloride (147 mL, 0.75 mol) was added. The mixture was stirred and allowed to warm up to room temperature overnight and filtered under argon to remove the precipitated lithium salts. The solvents were evaporated and the liquid residue was distilled, first using a Vigreux column, followed by spinning band distillation. The total MPTES obtained was 113.3 g (86% yield). This was identified by 1H NMR spectroscpy, IR (infrared) and GC/MS; (gas chromatography/mass spectroscopy) b.p. 59°-60°/0.15 mm Hg.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:21][CH2:20][C@:6]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:7]=[C:8]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:9][CH2:10][C@@H:5]2[CH2:4]1.C([BH-](CC)CC)C.[Li+]>O1CCCC1>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C@:6]12[CH2:20][O:21][C@@H:3]([CH3:2])[CH2:4][C@H:5]1[CH2:10][S:9][C:8]([NH:11][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[N:7]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CCl)C[C@H]2CS1)c1ccccc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
N-[(4aR,6R,8aS)-6-(Chloromethyl)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C21) (1.88 g, 4.30 mmol) was dissolved in tetrahydrofuran and cooled to 0° C. Lithium triethylborohydride (1 M in tetrahydrofuran, 34.4 mL, 34.4 mmol) was added drop-wise, and the reaction mixture was allowed to warm to room temperature. After 18 hours, the reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluent: dichloromethane, followed by a gradient of 0% to 10% methanol in dichloromethane) provided the product as a white solid. Yield: 1.40 g, 3.48 mmol, 81%. LCMS m/z 403.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 12.29 (br s, 1H), 8.19-8.30 (br m, 2H), 7.48-7.54 (m, 1H), 7.37-7.48 (m, 3H), 6.84-6.96 (m, 2H), 4.15 (dd, J=12.2, 2.0 Hz, 1H), 3.77-3.84 (m, 1H), 3.77 (d, J=12.3 Hz, 1H), 3.09-3.19 (br m, 1H), 3.01 (dd, J=12.9, 4.1 Hz, 1H), 2.63 (dd, J=12.8, 2.8 Hz, 1H), 1.88-2.00 (m, 1H), 1.62-1.69 (m, 1H), 1.30 (d, J=6.2 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][CH:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH2:5]([O:4][C:2]([NH:19][CH:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:24][CH:23]=1)[C:20]([OH:22])=[O:21])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(Br)cc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (8.65 mL, 61.5 mmol) was added to a refluxing solution of 4-bromo-dl-phenylalanine (15 g, 61.5 mmol) in ethyl acetate (250 mL). After stirring at reflux overnight, the reaction mixture was cooled to ambient temperature, filtered through celite and concentrated in vacuo to afford 2-{[(benzyloxy)carbonyl]amino}-3-(4-bromophenyl)propanoic acid which was used in the subsequent step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(F)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-fluorophenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[N+:19]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH3:12])([CH3:11])[CH:3]([CH3:13])[C:2]2([CH3:14])[CH3:1])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1C(C)(C)c2ccc([N+](=O)[O-])cc2C1(C)C
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
Into a 500 ml reaction vessel equipped with stirrer, thermometer, reflux condenser, addition funnel and cooling bath is placed 50 grams of 1,1,2,3,3-pentamethyl indane having the structure: ##STR36## in admixture with 100 grams of acetic acid. While maintaining the reaction mass at 25° C., 40 grams of fuming nitric acid is added over a period of 0.5 hour. The reaction mass is then stirred for a period of 6 minutes. Over a period of 10 minutes while maintaining the reaction mass at 20°-22° C., 10 grams of concentrated sulfuric acid is added to the reaction mass. The reaction mass is then heated to a temperature in the range of 26°-30° C. with stirring and maintained at that temperature for a period of four hours. At the end of the four hour period, the reaction mass is added to water and a solid is formed which precipitates out. The resulting crystals are washed with two 500 ml portions of water. The crystals melt at 99.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=O)[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:36][N:37]=[C:38]=[S:39].Cl>C([O-])([O-])=O.[K+].[K+]>[CH3:36][N:37]1[C:38](=[S:39])[NH:25][N:24]=[C:22]1[C:20]1[N:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[CH:21]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(-c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3)c(-c3ccccc3C(F)(F)F)n2)n[nH]c1=S
Temperature: 25 °C
Yield: 11.3 %

Procedure:
To a suspension of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (215 mg, 0.430 mmol) in 8 mL 10% K2CO3 solution was added methyl isothiocyanate (0.06 mL, 0.877 mmol) via syringe. The reaction was refluxed 12 h and cooled to room temperature. The reaction was neutralized at 0° C. with 1M HCl and then extracted 3×10 mL with ethyl acetate. The combined organic layers were dried with MgSO4 and the solvent removed in vacuo. The crude residue was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 4-methyl-3-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1H-1,2,4-triazole-5(4H)-thione (27 mgs, II %) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 13.89 (s, 1H), 8.37 (s, 1H), 8.15-8.14 (m, 1H), 8.05-8.02 (m, 1H), 7.93-7.89 (m, 2H), 7.85 (d, J=8.58 Hz, 2H), 7.75-7.73 (m, 1H), 7.72-7.68 (m, 2H), 7.62-7.59, (m, 1H), 7.41 (d, J=8.58 Hz, 2H), 3.78 (s, 3H), 3.28 (s, 3H); MS (ES): 556.0 [M+H]+ and 578.3 [M+Na]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH2:15][CH2:16][C:17]4[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:25])=O>C(#N)C>[Cl:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH2:15][CH2:16][C:17]4[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1C=CC2=CN=C(c3ccc(CO)cc3)N3CCC(=C23)N1
Solvent: CC#N
Product: O=C1C=CC2=CN=C(c3ccc(CCl)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared by reacting 500 mg (1.7 mmol) of alcohol 58a, suspended in 25 mL of acetonitrile with 4 equivalents of thionyl chloride. After complete conversion as determined by HPLC analysis the reaction was concentrated in vacuo and the crude benzylchloride was without further purification. HPLC Rt=3.060 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:19](B(O)O)=[CH:20][CH3:21].C(P(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd]Cl>[CH3:18][C:15]1[CH:16]=[CH:17][C:11]2[N:10]=[C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2](/[CH:19]=[CH:20]/[CH3:21])[N:3]=3)[NH:13][C:12]=2[CH:14]=1
Reactant: CC=CB(O)O
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Agent: Cl[Pd]Cl
Agent: CCP(CC)CC
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: C/C=C/c1cnc(N)c(-c2nc3ccc(C)cc3[nH]2)n1
Temperature: 120 °C
Yield: 31.4 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (50 mg, 0.1644 mmol), prop-1-enylboronic acid (15.53 mg, 0.1808 mmol), dichloropalladium; triethylphosphane (6.800 mg, 0.01644 mmol) and disodium carbonate (164.4 μL of 2 M, 0.3288 mmol) was dissolved in 1,2-dimethoxyethane (2 mL) and heated at 120° C. under microwave conditions 30 minutes. The residual solids were removed by filtration and the filtrate purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an orange solid (13.7 mg, 31% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.95 (3H, d), 2.45 (3H, s), 6.45-6.55 (1H, m), 6.8-6.9 (1H, m), 6.95 (0.5H, m), 7.05-7.15 (2H, m), 7.22 (0.5H, s), 7.45 (1H, br s), 7.55-7.6 (1H, m), 8.1 (1H, s), 13.15 (1H, vbr s) ppm; MS (ES+) 266.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:34])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCCCCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and heptane-1,7-diamine. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (dd, J=1.2, 0.8 Hz, 1 H), 7.97 (s, 1 H), 7.92 (d, J=7.6 Hz, 1 H), 7.74-7.68 (m, 2 H), 7.61-7.56 (m, 2 H), 5.91 (s, 1 H), 5.32 (s, 2 H), 4.52 (brs, 2 H), 3.75 (d, J=4.80 Hz, 2 H), 3.31 (d, J=1.60 Hz, 2 H), 2.94 (m, 2 H), 2.45 (s, 3 H), 1.72 (m, 4 H), 1.50 (m, 6 H).