Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH2:30]O)[CH:23]=1.N1CCCCC1>C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][CH:30]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[C:19]2=[O:20])[CH:23]=1
Reactant: OCCCc1cccnc1
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1SC(=CCCc2cccnc2)C(=O)N1CCCCOc1cccn2ccnc12

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 676 mg (5.0 mmol) of 3-(3-pyridyl)-1-propanol in 20 ml of ethanol, 43 mg (0.5 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1→25/1) to yield 0.49 g (23.0%, yellow oily substance) of the desired product.
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[CH3:8][N:9]([CH3:29])[CH2:10][CH2:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[C:21]([C:24]1[S:28][CH:27]=[N:26][CH:25]=1)(O)[CH3:22]>C(#N)C.ClCCl>[CH3:29][N:9]([CH3:8])[CH2:10][CH2:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[CH:21]([C:24]1[S:28][CH:27]=[N:26][CH:25]=1)[CH3:22]
Reactant: CN(C)CCc1sc2ccccc2c1C(C)(O)c1cncs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(c1cncs1)c1c(CCN(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of NaI (24 mg, 0.16 mmol)) and TMSCl (20 uL, 0.16 mmol) in acetonitrile (0.5 mL) was stirred for 15 min at room temperature. A solution of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-1-thiazol-5-yl-ethanol (Compound 17-1) (3 mg, 0.01 mmol) in dichloromethane (1.3 mL) was added and the reaction was stirred in a sealed vial at 100° C. for 3 hrs. The mixture was quenched with 1M Na2S2O3 until colorless and diluted NH4OH was added until pH ˜8. The product was extracted with EtOAc and the combined organic layers were washed with diluted NH4OH, concentrated and subjected to mass triggered preparative HPLC purification to afford dimethyl-{2-[3-(1-thiazol-5-yl-ethyl)-benzo[b]thiophen-2-yl]-ethyl}-amine (Compound 17-2). MH+=317.0, tR=4.24 min, (Method 2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[F:20])#[N:2].[OH-:22].[Na+].OO.Cl>C(O)C>[F:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:11]1[NH:2][C:1](=[O:22])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: [OH-]
Reactant: COc1cccc(F)c1C(=O)Nc1cc(C)ccc1C#N
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(F)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a suspension of N-(2-cyano-5-methylphenyl)-2-fluoro-6-methoxybenzamide (31.5 g, 111 mmol) in ethanol (626 mL) was added 6 M aqueous NaOH solution (205 mL). After 10 minutes, 30% aqueous H2O2 (60 mL) was added, forming a slurry. The reaction was heated to reflux for 18 h and cooled to room temperature. NaOH (22.2 g, 0.56 mol) and 30% aqueous H2O2 (26 mL) were added, and the reaction was heated to reflux for six hours. The reaction cooled to room temperature, 30% aqueous H2O2 (45 mL) was added, and the reaction was heated to reflux for 18 h. The reaction was cooled to room temperature, NaOH (10 g, 0.25 mol) and 30% aqueous H2O2 (70 mL) were added, and the reaction was heated to reflux for six hours. The reaction was cooled to room temperature and poured over ice (800 mL). The pH was adjusted to 3-4 by addition of conc. HCl solution, and the precipitated off-white solid was filtered and washed with water (3×40 mL). The solid was dried under vacuum to provide 2-(2-fluoro-6-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (28 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(C(=O)OC(C)(C)C)c2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cc(CBr)nc2ccccc12
Temperature: 90 °C
Reaction time: 5 h
Yield: 42.9 %

Procedure:
To a mixture of tert-butyl 2-methylquinoline-4-carboxylate (4.61 g) and carbon tetrachloride (50.0 mL) were added N-bromosuccinimide (3.71 g) and azobisisobutyronitrile (156 mg), followed by stirring at 90° C. for 5 hours. The reaction suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 2-(bromomethyl)quinoline-4-carboxylate (2.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28](CCOC3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N([CH2:70][CH2:71][CH2:72][S:73]([NH2:76])(=[O:75])=[O:74])=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:70][CH2:71][CH2:72][S:73]([NH2:76])(=[O:75])=[O:74])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: [N-]=[N+]=NCCCS(N)(=O)=O
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Product: Cc1ccc(-c2cn(CCCS(N)(=O)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (1.37 mmol) and compound 412 (2.79 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 65:35 to 85:15 as the eluent to afford the title compound as almost white solid. 13C NMR (DMSO-d6) δ 194.9, 158.8 (dd), 155.7 (dd), 149.4, 145.5, 139.9, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.4 (dd), 124.9, 124.1 (dd), 121.6, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 51.4, 47.9, 24.6, 19.4
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].I[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1>>[N+:15]([C:11]1[CH:10]=[C:9]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][C:2]2=[O:7])[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: O=C1CNCCN1
Product: O=C1CNCCN1c1cccc([N+](=O)[O-])c1

Procedure:
205 a) 1-(3-nitro-phenyl)-piperazin-2-one was prepared from piperazin-2-one (1.00 g, 9.99 mmol) and 1-iodo-3-nitro-benzene (3.00 g, 12.0 mmol) in a manner analogous to Example 204a. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.21 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 3.77 (t, J=4.9 Hz, 2H), 3.74 (s, 2H), 3.28 (t, J=4.8 Hz, 2H). MS=222 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(CO)cc(Br)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(COS(C)(=O)=O)cc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-bromo-6-methyl-pyridin-4-yl)-methanol (0.300 g, 1.48 mmol) in dichloromethane (2.0 mL) was added DIPEA (776 μL, 4.45 mmol). The resulting mixture was cooled to 0° C. and methanesulfonyl chloride (120 μL, 1.56 mmol) was added. After 1 hour, the reaction mixture was diluted CH2Cl2 (20 mL) and washed with saturated aqueous ammonium chloride (3×10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford methanesulfonic acid 2-bromo-6-methyl-pyridin-4-ylmethyl ester as crude product which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:10][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cccc(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(F)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
9.0 g (64 mmol) of 3-fluoro-2-hydroxybenzaldehyde are dissolved in 200 ml of DMF, 10.7 g (77.1 mmol) of potassium carbonate and 8.4 ml (12 g, 71 mmol) of benzyl bromide are added and the mixture stirred at 80° C. for 24 h. The mixture is poured into 600 ml of water, extracted several times with ethyl acetate, and the organic phase is dried over sodium sulfate, concentrated in vacuo and dried under high vacuum. The crude product is purified by silica gel chromatography (cyclohexane:ethyl acetate 2:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: COc1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 41.3 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.063 mMol) 4-methoxybenzoyl chloride, 6.9 mg (41%) of the title compound were recovered as a light brown foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(S(=O)(=O)Cl)ccc32)cc1
Solvent: c1ccncc1
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(S(=O)(=O)Nc4ccccc4)ccc32)cc1

Procedure:
2.33 g (6 mmol) of crude 1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline-6-sulphonylchloride are added dropwise, whilst cooling with ice, to a solution of 0.56 g of aniline in 15 ml of pyridine. Then the mixture is heated for 30 minutes to 100° C. and evaporated to dryness. The residue is chromatographed over a silica gel column with methylene chloride:ethyl acetate.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[C:102]([O:110][CH3:111])=[N:103][N:104]([CH2:106][CH2:107][CH2:108][OH:109])[CH:105]=2)=[CH:99][CH:100]=1>>[OH:109][CH2:108][CH2:107][CH2:106][N:104]1[CH:105]=[C:101]([C:98]2[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:100][CH:99]=2)[C:102]([O:110][CH3:111])=[N:103]1
Reactant: CNC(=O)c1nc(-c2cn(CCCO)nc2OC)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4OC)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 35 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 251 mg, 0.553 mmol) and 3-amino-6-[1-(3-hydroxypropyl)-3-methoxy-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 48C, 177 mg, 0.580 mmol) to afford 139 mg of the title compound (35%). 1H NMR (400 MHz, CD3OD) δ 8.90 (br. s., 1H), 8.33 (s, 2H), 7.85 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.02-7.07 (m, 1H), 6.90 (td, J=2.4, 8.1 Hz, 1H), 4.15 (t, J=6.7 Hz, 2H), 4.00-4.10 (m, 7H), 3.90 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 3.26 (s, 2H), 2.98 (s, 3H), 2.08 (quin, J=6.5 Hz, 2H), 1.20-1.27 (m, 6H). MS (ESI): m/z=723.42 [M+H]+. UPLC: tR=1.31 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [OH-].[Na+].[C:3]1(C)C=CC=CC=1.COS([O-])(=O)=O.[CH2:16]([O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:16]([O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][N:30]2[CH3:3])=[CH:26][CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COS(=O)(=O)[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Product: Cn1ccc2ccc(OCc3ccccc3)cc21

Procedure:
To 125 g of caustic soda in pellets in 125 ml water are added 300 ml toluene, 50 ml methylsulphate and 7.36 g tetrabutylammonium hydrogensulphate, then, with stirring, 0.33 mole (73.6 g) 6-benzyloxyindole. Stirring is maintained for 15 minutes after the end of the evolution of heat. The reaction medium is diluted with two volumes of water. After separation of the organic phase the aqueous phase is extracted with toluene. After washing the organic phases with water and drying them, the desired product is obtained by evaporation. It melts at 79° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)NCCc1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 71.7 %

Procedure:
tert-Butyl 2-(2-cyano-4-pyridyl)ethylcarbamate (3.0 g, 12 mmol) and methyl thiosalicylate (3.6 g, 21 mmol) were dissolved in toluene (12 ml), and triethylamine (6.0 ml, 43 mmol) was added thereto. The mixture was refluxed for 8 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:1, v/v) were collected, concentrated and recrystallized from hexane-ethanol to give the titled compound (3.3 g, 71%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 3-bromopyridine according to the general procedure C. Obtained as a yellow solid (587 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1.[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(Br)c(OC2CCCCO2)c1

Procedure:
To solution of 4-bromo-3-hydroxybenzoic acid (G.1) (available from Combi-Blocks Inc.) (2.50 g, 115 mmol) in DCM (100 mL) at 23° C., was added 3,4-dihydro-2H-pyran (2.10 mL, 23.0 mmol) followed by PPTS (0.289 g, 1.15 mmol). The reaction gave a mixture of bis THP protected compound and G.2.
Reaction SMILES: [C:1]([O:7]C)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].CO.[C:13](#[N:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:15][CH:14]([C:1](=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]#[N:16]
Reactant: COC(=O)C(C)(C)C
Reactant: CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C#N)C(=O)C(C)(C)C

Procedure:
234.6 grams (2 moles) of methyl pivalate and 120 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) were heated to 90° C. in 1500 ml of dry toluene. There were dropped in at this temperature after addition of 1 ml of methanol 233.3 grams (2 moles) of propionitrile within 2.5 hours. After the end of the development of hydrogen the suspension was extracted with a total of 1200 ml of water and after phase separation the aqueous phase was acidified with concentrated HCl to a pH of 2. The deposited oil was separated off, the water phase extracted with chloroform, the organic extracts combined, dried and concentrated. The residue was fractionated in a water jet vacuum. 2,4,4-trimethyl-3-oxopentanenitrile came over at 87° C./11 Torr in an amount of 226.1 grams (81.2% of theory).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH2:21][CH3:22])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Yield: 74 %

Procedure:
3.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III) from Example 4, 30 ml of ethanol, and 0.3 ml of concentrated sulfuric acid were added into 100 ml three-necked flask, and refluxed until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with 10 ml×3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 2.5 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 74%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25].[I-:26].[Na+]>C(C(C)=O)C>[I:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1c(OCCCCl)ccc2c1OC(CCC(=O)OCC)CC2
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OCC)CC2

Procedure:
Ethyl 7-(3-chloropropoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoate (3.2 g, 9.042 mmol) and sodium iodide (13.6 g, 9.042 mmol) were added to 200 ml of methyl ethyl ketone and the reaction mixture was heated to reflux overnight. The solvent was removed under vacuum and 100 ml of water was added. The solution was extracted 3 times with ethyl acetate. The combined extracts were dried and filtered, and the solvent was removed under vacuum to give the product as a brown oil.
Reaction SMILES: O[C@H:2]1[CH2:7][C@@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.C(P(CCCC)CCCC)CCC.[CH2:27]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:32])=[O:31])[CH3:28]>>[CH2:27]([N:29]([C@H:2]1[CH2:7][C@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2)[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:31])=[O:32])[CH3:28]
Reactant: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C[C@@H]1C[C@H](O)c2ccsc2S1(=O)=O
Agent: CCCCP(CCCC)CCCC
Product: CCN([C@H]1C[C@H](C)S(=O)(=O)c2sccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 4 h
Yield: 20.4 %

Procedure:
cis-4-hydroxy-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide (5 g), tributylphosphine (6.6 mL) and N-ethyl-2-nitrobenzenesulfonamide (6.17 g) are mixed under nitrogen atmosphere. It is cooled at −20/−30° C. Diisopropyl azadicarboxylate (4.8 mL) is added, maintaining the temperature. It is maintained under stirring, maintaining the temperature, for 4 hours. Tributylphosphine (1.5 mL) and diisopropyl azadicarboxylate (1.5 mL) are added. It is left to reach 20-25° C. and maintained for 30 minutes. It is cooled at 0-5° C.; it is filtered, washed with cold toluene and dried. After purifying by resuspension in methanol, 2.01 g of trans-4-[N-ethyl-N-(2-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][CH3:24])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]([F:22])[F:21])[CH:11]=3)=[CH:4][CH:3]=1.[CH2:25]([N:28]=[C:29]=[O:30])[CH2:26][CH3:27].C(N(CC)CC)C>ClCCCl>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH:20]([F:22])[F:21])=[CH:13][CH:14]=2)[N:9]([CH2:23][CH3:24])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([NH:28][CH2:25][CH2:26][CH3:27])=[O:30])=[CH:3][CH:4]=1)#[N:18]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC(F)F)cc21
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCNC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC(F)F)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (200 mg, 0.611 mmol) in 1,2-dichloroethane (2 mL) is treated with n-propylisocyanate (115 mL, 1.23 mmol) and triethylamine (170 mL, 1.22 mmol). The resulting solution is stirred at ambient temperature for 12 hours, and then concentrated. The residual material is separated by silica gel chromatography (1/2 ethyl acetate-hexane) to afford the title product as a solid.