Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>ClCCl>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution containing 50 g (531 mmol) of 3-aminopyridine and 139 mL (797 mmol) of N,N-diisopropylethylamine in 800 mL of dichloromethane at 0° C. was carefully added through an addition funnel 72 mL (584 mmol) of pivaloyl chloride. The reaction mixture was stirred at 0° C. for 30 min then concentrated in vacuo. To the residue was added 600 mL of ethyl acetate and the organic solution was washed sequentially with water, 0.5N aqueous sodium bicarbonate solution and saturated aqueous brine (300 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. To the crude solid was added 150 mL of ethyl acetate. The mixture was stirred vigourously for 30 min, then 300 mL of hexane was added and the mixture was stirred for an additional 30 min. The resultant crystalline solid was filtered and washed with 400 mL of 10% ethyl acetate/hexane to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.57 (d, J=2.5 Hz, 1H), 8.36 (dd, J=4.8, 1.4 Hz, 1H), 8.21-8.19 (m, 1H), 7.47 (br s, 1H), 7.30-7.27 (m, 1H), 1.36 (s, 9H).
Reaction SMILES: [C:1]1([N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[Si](C)(C)C)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([CH:47]=O)[CH:41]=[CH:40]2>O1CCCC1>[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42](/[CH:47]=[C:14](/[C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:13][CH:12]=1)\[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:41]=[CH:40]2
Reactant: C[Si](C)(C)C(c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccc2cc(/C=C(\c3ccccc3)c3ccc(N(c4ccccc4)c4ccccc4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
N,N-diphenyl-4-(phenyl(trimethylsilyl)methyl) aniline (5.0 g, 12.3 mmol) was dissolved in purified tetrahydrofuran (30 mL) under a nitrogen atmosphere, and n-butyllithium (8.4 mL, 13.5 mmol) was slowly added thereto at −78° C. The reaction mixture solution was stirred at room temperature for 8 hours. 6-bromo-2-naphthaldehyde (2.9 g, 12.3 mmol) dissolved in tetrahydrofuran (10 mL) was added thereto at room temperature. The reaction mixture solution was stirred at room temperature for 24 hours. The reaction mixture solution was subjected to extraction with dichloromethane and distilled water, and the extracted material is subjected to column chromatography (hexane:dichloromethane=9:1). The reaction solvent was removed, and then the residue material was dried in vacuum to thereby obtain a pale yellow solid (4.5 g, yield: 66%).
Reaction SMILES: [NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([N:47]1[CH2:61][CH2:60][CH2:59][C@H:48]1[C:49]([O:51]CC1C=CC=CC=1)=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])=[O:35])[CH3:33])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N(C(OC(C)(C)C)=O)[C@H](C(NCC(O)=O)=O)C>>[NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([N:47]1[CH2:61][CH2:60][CH2:59][C@H:48]1[C:49]([OH:51])=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])=[O:35])[CH3:33])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C

Procedure:
The above peptide XV was hydrogenated as described for the preparation VIII to obtain the product in quantitative yield. Rf3 0.22. Anal. calcd. for C40H61N9O12:C 55.66, H 7.12, N 14.60%. Found: C 55.86, H 7.23, N 14.14%.
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].Cl[C:8]1[CH:13]=[C:12](Cl)[C:11](Cl)=[CH:10][C:9]=1Cl>CN(C=O)C>[C:3]([S:6][C:8]1[CH:13]=[C:12]([S:6][C:3]([CH3:5])([CH3:4])[CH3:2])[C:11]([S:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[CH:10][C:9]=1[S:6][C:3]([CH3:5])([CH3:4])[CH3:2])([CH3:5])([CH3:4])[CH3:2]
Reactant: CC(C)(C)S
Reactant: Clc1cc(Cl)c(Cl)cc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1cc(SC(C)(C)C)c(SC(C)(C)C)cc1SC(C)(C)C
Temperature: 0 °C
Yield: 69 %

Procedure:
Sodium (9.3 g, 0.18 mol) was added to a degassed solution of 2-methyl-2-propanethiol (20.9 mL, 0.18 mol) in dry DMF (105 mL), under stirring at 0° C. in nitrogen atmosphere. The mixture was allowed to reach room temperature (RT, 20-25° C.) and stirred overnight. 1,2,4,5-Tetrachlorobenzene (8.0 g, 0.037 mol) was then added and the resulting mixture was stirred at RT for 2 h and then gently refluxed for 18 h. After cooling at RT, the reaction mixture was poured over ice (100 g), the precipitate was removed by filtration, washed with water, and dried to give 11.0 g of the title compound as an off-white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=C2N=NN(O)C2=CC=1.N.C(N(CC)CC)C.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[CH:45][C:46]=1[CH3:47]>ClCCl>[CH3:47][C:46]1[CH:45]=[C:44]([CH3:48])[NH:43][C:42](=[O:49])[C:41]=1[CH2:40][NH:39][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:14][C:15]2[CH:20]=[N:19][CH:18]=[N:17][CH:16]=2)[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1cncnc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(Cc3cncnc3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A mixture of 2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxylic acid (60 mg, 0.22 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (65 mg, 0.34 mmol), N-hydroxybenzotrizole (180 mg, 1.33 mmol) and triethylamine (46 mg, 0.34 mmol) in dichloromethane (30 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethyl pyridin-2-ol (33.44 mg, 0.22 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (20 mL×3). The organic layer was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxamide (17 mg, 19%). LRMS (M+H+) m/z: calcd 401.19. found 401. HPLC purity (214 nm): 92%. 1H. NMR (300 MHz, CD3OD): δ 9.03 (s, 1H), 8.43 (s, 2H), 7.80-7.78 (m, 1H), 7.39-7.36 (m, 1H), 7.19-7.16 (m, 2H), 5.56 (s, 2H), 4.55 (s, 2H), 2.62 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[CH:22]2>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][N:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Brc1ccc2ncncc2c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ncncc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromoquinazoline (188 mg, 0.9 mmol; Parkway Scientific) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.22 (m, 4H) 2.42 (s, 3H) 2.91-3.01 (m, 1H) 3.06-3.32 (m, 4H) 4.33 (s, 2H) 6.92-6.99 (m, 1H) 7.02-7.09 (m, 1H) 7.23 (s, 1H) 7.99 (dd, J=9, 2 Hz, 1H) 8.12 (d, J=2 Hz, 1H) 8.22 (d, J=9 Hz, 1H) 9.33 (s, 1H) 9.63 (s, 1H); MS (DCI/NH3) m/z 355 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][N:35]([CH3:41])[S:36]([CH:39]=[CH2:40])(=[O:38])=[O:37]>>[CH3:34][N:35]([CH3:41])[S:36]([CH2:39][CH2:40][N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:38])=[O:37]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: C=CS(=O)(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(=O)(=O)N(C)C)C3)ccc1-2
Yield: 75 %

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and ethenesulfonic acid dimethylamide were reacted. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 2% MeOH in DCM) to give 443 as a beige solid (117 mg, 75%). LCMS: RT=7.69 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=8.17 Hz), 7.89 (1 H, s), 7.08 (1 H, dd, J=8.21, 1.86 Hz), 6.99-6.96 (1 H, m), 5.92-5.83 (1 H, m), 4.38 (2 H, t, J=5.05 Hz), 3.77 (2 H, t, J=6.90 Hz), 3.74-3.64 (1 H, m), 3.39 (2 H, t, J=5.06 Hz), 3.23 (2 H, t, J=6.67 Hz), 3.00-2.92 (4 H, m), 2.87 (6 H, s), 1.60 (6 H, d, J=6.64 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:27]6[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=6[F:25])[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1F
Yield: 65.5 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol), 1-(2,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (97.4 mg, 0.367 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (105 μL, 0.612 mmol) and HATU (151 mg, 0.40 mmol) and in the same manner as in Example 65, the title compound (115 mg, 66%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:9]=2)[C:4](=[O:22])[NH:3]1.[H-].[Na+].I[CH3:27]>CN(C=O)C>[CH3:27][N:3]1[C:2]([CH3:23])([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:9]=2)[C:4]1=[O:22]
Reactant: CC1(C)CCN(c2cnc(C#Cc3ccccc3)cn2)C(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cnc(C#Cc3ccccc3)cn2)CCC1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of 4,4-dimethyl-1-(5-(phenylethynyl)pyrazin-2-yl)tetrahydropyrimidin-2(1H)-one (Example 164, step 2) (30 mg, 0.098 mmol) in 2 ml of DMF was added 60% sodium hydride suspension (4.7 mg, 0.118 mmol, 1.2 equiv.). After stirring at room temperature for 15 min, iodomethane (7.4 ml, 16.7 mg, 0.118 mmol, 1.2 equiv.) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and was worked up with ethyl acetate/water. Flash chromatography over a prepacked 20 g silica column eluting with a heptane to 50% ethyl acetate in heptane gradient yielded the title compound (25.4 mg, 81% yield) as an off-white solid, MS: m/e=321.3 (M+H+).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[F:8][C:9]([F:32])([F:31])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:29]\O)/[C:25]([O:27][CH3:28])=[O:26])[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:31][C:9]([F:8])([F:32])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:29]\[O:6][CH3:7])/[C:25]([O:27][CH3:28])=[O:26])[CH:13]=[CH:12][CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)/C(=C/O)c1ccccc1COc1cccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dimethyl sulphate (0.65 ml, 6.9 mmol) was added dropwise to a mixture of (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (2.12 g, 6 mmol) and anhydrous potassium carbonate (1.2 g, 8.7 mmol) in dry DMF (10 ml). After stirring at room temperature for 6 hours, the mixture was poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and concentrated to give a crude product which was purified by column chromatography (silica eluted with 20% ethyl acetate in hexane) to give (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-methoxyacrylate (Compound No.177 in Table I of EP-A-0278595); (1.01 g, 46%) as a cream solid; mp 73-74° C.; 1H NMR (270 MHz)δ: 3.68(3H,s), 3.82(3H,s), 5.34(2H,s), 6.87(1H,d), 7.15-7.70(6H,m), 7.55(1H,s) ppm.
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].Cl>CS(C)=O>[F:1][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13]
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1F
Temperature: 140 °C
Reaction time: 10 h
Yield: 81.9 %

Procedure:
Cesium fluoride (97.5 g, 642 mmol) was added under nitrogen atmosphere to a solution of 2-chloro-1-methyl-3-nitrobenzene (73.4 g, 428 mmol) in DMSO (185 mL), and the mixture was stirred at 140° C. for 10 hours. The reaction mixture was then poured into 0.5N hydrochloric acid and extracted twice with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude product was obtained by vacuum concentration, and then purified by reduced-pressure distillation (boiling point: 118° C. to 122° C./15 mm Hg) to yield the title compound (54.4 g, 82%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)(=[O:26])=[O:25])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1c[nH]c(-c2cccnc2Cl)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccc(F)c2)c1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a solution of 5-(2-chloropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (25 mL) was added sodium hydride (60% in oil, 73 mg) at room temperature and the mixture was stirred for 15 min. 3-Fluorobenzenesulfonyl chloride (310 mg) was added to the reaction mixture, and the mixture was further stirred for 30 min. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 420 mg, 95%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:5]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:16][CH:17]=1
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Yield: 50.3 %

Procedure:
A solution of 1-methyl-4-(4-nitrophenoxy)-4-phenylpiperidine (4.4 g, 14.1 mM) in methanol (250 ml) was hydrogenated at 1 atmosphere and ambient temperature over 5% palladium on charcoal (500 mg) until the theoretical uptake of hydrogen had occurred (about 2 hours). The catalyst was removed by filtration and the solvent evaporated under reduced pressure. Recrystallisation of the residue from IPA gave the title compound (2 g) m.p. 174°-5°.
Reaction SMILES: C(O[C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](C(F)(F)F)[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([Br:25])[CH:6]=1)C.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Br:25][C:7]1[CH:6]=[C:5]([C:4]([N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:26])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]=1[O:21][CH2:22][CH2:23][OH:24]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CNCCCCCCCCc1ccccc1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(Br)c(OCCO)c(-c2ccccc2)c1

Procedure:
5-bromo-6-(2-hydroxyethoxy)-N-methyl-N-(8-phenyloctyl)[1,1′-biphenyl]-3-carboxamide was prepared as a colorless oil (0.200 g, 56%) from 3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ 7.87–7.54 (m, 5H); 7.38–7.12 (m, 6H); 3.65 (m, 4H); 3.50 and 3.03 (2bt, 2H); 3.03 (2s, 3H); 2.58 (m, 2H); 1.98 (bs, 1H); 1.60 (m, 4H); 1.40–1.22 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:11][CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][CH:14]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:12][CH3:11]
Reactant: CCCC(=O)CCC
Reactant: NCCc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCC(CCC)NCCc1ccccc1Br
Reaction time: 20 h

Procedure:
10 g of 2-bromophenethylamine and 5.71 g of 4-heptanone are dissolved in 250 cm3 of 1,2-dichloroethane at a temperature close to 20° C. 14.84 g of sodium triacetoxyborohydride and 2.9 cm3 of glacial acetic acid are added to the reaction medium. Stirring is continued for 20 h. 300 cm3 of 1M sodium hydroxide are added to the reaction medium. The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate. The organic phases are combined and washed with 4 lots of 100 cm3 of water then 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated using a rotary evaporator under reduced pressure (5 kPa). The yellow liquid obtained is purified by flash chromatography over silica (column: 400 g; particle size: 20-40 μm, spherical; flow rate: 30 cm3/min; eluent: 100% heptane to 70% ethyl acetate/30% heptane gradient). After concentrating the fractions under reduced pressure, 17.33 g of N-[2-(2-bromophenyl)ethyl]heptan-4-amine are obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](N)[CH2:9][NH2:10].C=O>C(Cl)Cl>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:8][CH2:9][NH:10]1
Reactant: NCCN
Reactant: Oc1ccccc1
Agent: C=O
Solvent: ClCCl
Product: c1ccc2c(c1)CCNO2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer is charged 450 parts phenol, 450 parts methylene chloride and 144 parts of ethylene diamine. The temperature of the reaction mixture is adjusted to 25° C. and 595 parts of 50% formalin is added while maintaining the temperature below 30° C. The reaction mixture is stirred for 2 hours at 30° C. after formaldehyde addition is complete. It is then heated to atmospheric reflux, refluxed for 3 hours and allowed to cool and separate into two layers. The upper water layer is withdrawn and discarded. The lower organic layer is reheated to atmospheric reflux and distilled to remove solvent. Heating is continued with the gradual reduction of pressure until a temperature of 70° C. at about 5.0 kPa pressure is reached. Cellosolve (450 parts) is added to the resin slowly, keeping the temperature near 70° C. A uniform yellow solution forms which is cooled and filtered. The product has 66% closed dihydroxybenzoxazine ring and a calculated equivalent wt. of 224. The solution has a solids content of 60.2%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[S:12](=[O:22])(=[O:21])[NH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:16])[C:3]1=2.[OH-].[Na+].[CH3:25]I>CO>[OH:16][C:15]1[C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=3[C:4]=2[S:12](=[O:22])(=[O:21])[N:13]([CH3:25])[C:14]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CI
Reactant: COC(=O)C1=C(O)c2c(c3cc(C)ccc3n2C)S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(O)c2c(c3cc(C)ccc3n2C)S(=O)(=O)N1C
Yield: 84.6 %

Procedure:
1.7 gm of methyl 2,5-dihydro-5,8-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide were reacted analogous to Example 18(f) with 5.3 ml of 1 N sodium hydroxide and 2.6 gm of methyl iodide in 20 ml of methanol to yield 1.5 gm (84% of theory) of methyl 2,5-dihydro-4-hydroxy-2,5,8-trimethyl-1,2-thiazino [5,6-b]indole-3-carboxylate-1,1-dioxide; M.p.: 144°-145° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3].C([O:34][C@@H:35]([CH3:39])[C:36](Cl)=[O:37])(=O)C>>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:13]2[NH:20][C:19]([CH3:21])=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([C:36](=[O:37])[C@@H:35]([OH:34])[CH3:39])[CH2:29][CH2:30]3)=[O:23])[C:14]=2[N:15]=[CH:16][N:17]=1)[CH3:3]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Agent: Cl
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)[C@H](C)O)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f17) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.