Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12](=[O:30])[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:15])[CH3:14].C(OCC)(=O)C>C(O)(=O)C>[CH3:10][O:11][C:12](=[O:30])[C:13]([C:16]1[CH:21]=[C:20]([N+:6]([O-:9])=[O:7])[CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:15])[CH3:14]
Reactant: COC(=O)C(C)(C)c1ccccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a mixture of sulfuric acid (0.27 ml) and nitric acid (0.34 ml), a solution of the compound (1.0 g) obtained in Example 561 in acetic acid (30 ml) was added dropwise at 5° C. The reaction mixture was stirred at 45° C. for 4 h, poured into ice cold water and ethyl acetate was added to the mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=9:1) to give 530 mg of the titled compound (yield, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[NH4+].[Cl-]>[Fe]>[NH2:20][C:18]1[CH:17]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: CNC(=O)c1ccc(COc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CNC(=O)c1ccc(COc2cc(N)cc(Cl)c2)cc1

Procedure:
The product from Example 195c was reduced with Fe and NH4Cl following the procedure from Example 237E to give the title compound.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6](C)[CH2:7][CH2:8][CH2:9][CH2:10]O)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.NCCCCC[CH2:25][OH:26].C1(=O)OC(=O)C2=CC=CC=C12>>[C:4]1(=[O:13])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:25][OH:26])[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]12
Reactant: CC(CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: NCCCCCCO
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCCCCCO
Yield: 91 %

Procedure:
This compound was prepared in the same manner as 5-phthalimidohexanol from 6-aminohexanol (3.51 g, 30.0 mmol) and phthalic anhydride (4.44 g, 30.0 mmol) to give the product as brown oil: yield 91%; 1H NMR (CDCl3) δ 1.3-1.8 (m, 8H), 3.6-3.7 (m, 4H), 4.3 (t, J=6.5 Hz, 1H), 7.7 (m, 2H), 7.8 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].CCCC[Sn]([C:25]1[N:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(CCCC)CCCC>C1COCC1.CN(C=O)C>[F:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][N:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1

Procedure:
A mixture of 2-bromo-1-fluoro-4-nitrobenzene (2.0 g, 9.1 mmol) and 2-(1,1,1-tributylstannyl)pyridine (3.36 g, 9.11 mmol) in THF (80 ml) and DMF (10 ml) was degassed with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (200 mg, 3 mol %) was added, and the mixture was heated at reflux for 24 h. More 2-bromo-1-fluoro-4-nitrobenzene (0.60 g, 2.7 mmol) and catalyst (100 mg, 1.5 mol %) were added, and the mixture was heated as before for another 24 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 50% dichloromethane in isohexane, then 100% dichloromethane, then 100% ethyl acetate (UV detection). 2-(2-Fluoro-5-nitrophenyl)pyridine was isolated as a colourless solid (2.11 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.30-7.37 (2H, m), 7.80-7.87 (2H, m), 8.27 (1H, m), 8.78 (1H, m), 9.01 (1H, dd, J 3.1, 6.7 Hz); MS (ES+) m/z 219 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][CH2:5][O:4][C:3]=1[C:8](=[O:13])C(F)(F)F.[OH-:14].[K+].Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:7][CH2:6][CH2:5][O:4][C:3]=1[C:8]([OH:13])=[O:14]
Reactant: [OH-]
Reactant: CC1=C(C(=O)C(F)(F)F)OCCO1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)O)OCCO1
Yield: 69.4 %

Procedure:
A mixture of 1-(5,6-dihydro-3-methyl-1,4-dioxin-2-yl)-2,2,2-trifluoroethanone (12 g, 0.06 mole) and powdered potassium hydroxide (6 g, 0.1 mole) was refluxed in toluene (200 ml) for 7 hours. The mixture was cooled, acidified with 6N hydrochloric acid, and the solid precipitate, crude 5,6-dihydro-3-methyl-1,4-dioxin-2-carboxylic acid (6 g, 60% yield) collected.
Reaction SMILES: B.CSC.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([NH2:21])=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>O1CCCC1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH2:21])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N2CCC(C(N)=O)CC2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(N2CCC(CN)CC2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
Borane-dimethyl sulphide complex (15 ml; 10M in dimethyl sulphide) was added dropwise at 15°-20° C., under nitrogen, to a stirred suspension of 1-(4-methoxyphenyl) piperidine-4-carboxamide (10 g) in tetrahydrofuran (95 ml). The mixture was heated under reflux for 4 hours then allowed to stand at ambient temperature for 16 hours. Ice water was added to destroy excess reducing agent then the mixture was acidified by the addition of hydrochloric acid (5M) and washed with ether (200 ml). The aqueous layer was basified by the addition of concentrated aqueous sodium hydroxide solution then the product was extracted into ether (3×250 ml). The combined extracts were dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of dichloromethane and industrial methylated spirit as eluant. The solvents were removed in vacuo from the appropriate fractions to give 1-[1-(4-methoxyphenyl)-piperid-4-yl]methylamine as an oil (0.5 g).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][S:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:35])=[O:2])=[CH:9][CH:8]=3)=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:21]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(SCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(SCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.9 %

Procedure:
To a stirred solution of [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethylsulfanyl}-benzoic acid methyl ester (22 mg, 0.043 mmol) in MeOH (5 ml) was added NaOH (5.18 mg, 0.129 mmol) in water (2 ml) dropwise at 0° C. The reaction mixture was then stirred at rt for 14 hours. After the completion of the reaction (monitored through TLC), MeOH was concentrated in vacuo, diluted with H2O (7 ml) and the aqueous layer was acidified (pH ˜2-3) with 2 N HCl and then extracted with EtOAc (3×7 ml). Combined organic layers were washed with brine (8 ml) and finally dried over Na2SO4. Organic layer was distilled under reduced pressure to get off white solid (20 mg), which was purified by column chromatography [SiO2 (230-400 mesh), DCM:MeOH 98.0/2.0] to give the title compound (18 mg, 84.1%) as a off white solid. MS: m/e=495.0 [M+H±].
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li]CCCC.[CH3:34][O:35][C@H:36]1[C@@H:41]([CH3:42])[CH2:40][O:39][C@H:38]([CH:43]=O)[C@@H:37]1[O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Si:46]([O:45][C@@H:37]1[C@@H:36]([O:35][CH3:34])[C@@H:41]([CH3:42])[CH2:40][O:39][C@H:38]1/[CH:43]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48]
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C=O)OC[C@@H]1C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a stirred solution of n-octyltriphenylphosphonium bromide (2124 mg) in dry THF (10 ml) and dry HMPA (5 ml), there was added n-BuLi (4.0 ml, 1.6M in n-hexane) at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (2S,3R,4S,5S)-4-methoxy-5-methyl-3-(tert-butyldimethylsilyloxy)tetrahydro-2H-pyran-2-carbaldehyde (497 mg) in dry THF (3 ml) was added to the resulting orange solution. The mixture was stirred at 0° C. for 30 min, and at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined ethereal extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography gave (2S,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran (602 mg, 72% yield).
Reaction SMILES: [C:1]([C@@H:3]([NH2:23])[C@@H:4]([CH3:22])[C@@H:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:2]>C(Cl)(Cl)Cl>[C:1]([CH:3]([NH2:23])[C@@H:4]([CH3:22])[C@@H:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)#[N:2]
Reactant: C[C@H]([C@H](N)C#N)[C@H](CCc1ccccc1)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H](C(N)C#N)[C@H](CCc1ccccc1)OCc1ccccc1

Procedure:
(1S,2R,3S)-1-cyano-2-methyl-3-benzyloxy-N-benzylbutylamine (1S)-(15) [α]D=−12° (c 3.6; CHCl3); IR (CHCl3) 3343, 3090, 3068, 3031, 3013, 2979, 2935, 2880, 2226, 1605, 1587, 1497, 1455, 1386, 1378, 1359, 1333, 1232 cm−1; 1H NMR (250 MHz, CDCl3) δ 7.34 to 7.22 (m, 10H); 4.59 (d, J=11.2 Hz, 1H); 4.37 (d, J=11.2 Hz, 1H); 4.04 (d, J=12.8 Hz, 1H); 3.97 (d, J=4.7 Hz, 1H); 3.79 (d, J=12.8 Hz, 1H); 3.50 (dq, J=8.8; 6.1 Hz, 1H); 2.07 to 1.93 (m, 1H); 1.62 (broad s, 1H, NH); 1.22 (d, J=6.0 Hz, 3H); 1.04 (d, J=6.9 Hz, 3H); 13C NMR (62.5 MHz, CDCl3) δ 138.3; 138.0; 128.4; 128.3; 127.6; 127.5; 127.4; 119.1; 76.0; 70.8; 51.9; 51.5; 42.4; 16.4; 11.7; MS (CI) m/z 309 [M+H]+. HRMS: calculated for C20H25N2O (M+H), 309.19668; found, 309.19321.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[OH:13])[CH:11]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccccc1-c1cc(Cl)c2ccccc2n1
Yield: 52.4 %

Procedure:
2,4-Dichloroquinoline (0.500 g, 2.525 mmol), 2-hydroxyphenylboronic acid (0.332 g, 2.405 mmol), sodium carbonate (0.510 g, 4.810 mmol) and Pd(PPh3)4 (0.139 g, 120 mmol) were added to a degassed mixture of toluene (5 mL) and water (2 mL), and the mixture was heated for 15 hours. After cooling, water (100 mL) was added and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography (dichloromethane) to give the title compound (0.322 g, 50%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>CO>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=[C:15]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cnc(N2CCC(CC(=O)O)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Yield: 82.8 %

Procedure:
To a suspension of 1.41 g (2.94 mmol) of [3′-(3-Chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 1:1 mixture of water:methanol (30 mL) is added 4.0 mL (10 mmol) of sodium hydroxide as a 10% aqueous solution. After stirring at room temperature overnight the methanol is removed under reduced pressure and the pH of the resulting solution is adjusted to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 1.10 g (82.9%) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as an orange oil.
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of DMF (50 mL) was added 1-bromo-2-nitro-4-chloro-benzene (5.0 g, 21.1 mmol), phenol (1.9 g, 21.1 mmol), and Na2CO3 (2.3 g, 21.1 mmol). The solution was heated to 85° C. and stirred overnight. The reaction was poured into water and extracted with EtOAc. Washed with water and dried over Na2SO4, filtered and concentrated under vacuum giving a yellow oil that was purified by silica gel column chromatography eluting with Hexanes:Ethyl Acetate (90:10) to give 4-chloro-2-nitro-1-phenoxy-benzene (3.8 g, 74%). 4-Chloro-2-nitro-1-phenoxy-benzene (13 g, 52.1 mmol) was reacted with SnCl2 (49.3 g, 260 mmol) following the procedure from Example 7f giving 5-chloro-2-phenoxy-phenylamine as a white solid 9.0 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[N:7][CH:6]=[CH:5][N:4]=1.[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COc1nccnc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nccnc1CBr

Procedure:
2-methoxy-3-methylpyrazine (0.943 mL, 8.06 mmol), N-bromosuccinimide (1.505 g, 8.46 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.132 g, 0.806 mmol) were heated at reflux in CCl4 (65.5 mL) (oil bath=100° C.) for 2.5 h. LCMS indicated formation of the product. The crude mixture was cooled, filtered and purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a CH2Cl2/hexanes mixture (0% to 100%). Related fractions were pooled and co-evaporated with toluene to afford a toluene solution (30 mL) of the product. To be used as it was for next step.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1C1C=CC=CC=1.[CH:18]1[CH2:23][CH2:22][CH:21](C(O)=O)[CH2:20][CH:19]=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28].O>C(O)(=O)C.C(OCC)C>[CH3:17][C:16]1[C:4]2[O:3][C:2]([N+:27]([O-:32])=[O:28])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1CC=CCC1
Reactant: Cc1cccc2c(-c3ccccc3)c(Br)oc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: Cc1cccc2c1OC(c1ccccc1)([N+](=O)[O-])C2

Procedure:
A solution of 82.7 g (0.288 mole) of 2-bromo-7-methyl-3-phenylbenzofuran and 18.1 g (0.144 mole) of cyclohexene-4-carboxylic acid in 500 ml of acetic acid is treated over about 30 minutes with 13.2 g (0.144 mole) of dinitrogen tetraoxide in 20 ml of acetic acid. After about two hours 21.8 g (0.173 mole) of cyclohexene-4-carboxylic acid and 15.9 g (0.173 mole) of dinitrogen tetroxide in 25 ml of acetic acid is added. After about 5 additional hours the reaction mixture is poured into cold water to give the crude product as a gum. Trituration with diethyl ether gives a solid which is recrystallized from cyclohexane and carbon tetrachloride to provide yellow solid 7-methyl-2-nitro-2-phenylbenzofuran, m.p. 122°-126° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][CH2:29][N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH:32]([NH:40][C:41]([C:43]2[NH:47][C:46]3[S:48][C:49]([Cl:51])=[CH:50][C:45]=3[CH:44]=2)=[O:42])[C:31]1=[O:52])(C(C)(C)C)(C)C>C1COCC1>[Cl:51][C:49]1[S:48][C:46]2[NH:47][C:43]([C:41]([NH:40][CH:32]3[CH2:33][C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:30]([CH2:29][CH2:28][CH2:27][OH:26])[C:31]3=[O:52])=[O:42])=[CH:44][C:45]=2[CH:50]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NC1Cc2ccccc2N(CCCO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reaction time: 48 h
Yield: 86.5 %

Procedure:
TBAF (1.0 M in THF, 4.92 mL, 4.92 mmol) was added to N-[1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 20, 1.84 g, 3.56 mmol) in THF (15 mL) and the reaction was stirred for 48 hours. The reaction was quenched by the addition of EtOAc (50 mL) and NH4Cl (aq.) (20 mL) and the organic layer was dried (MgSO4), filtered and evaporated. Purification by column chromatography afforded the title compound (1.24 g, 3.08 mmol, 86%) as a white solid.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:28]=[CH:27][C:14]([CH2:15][C:16]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[S:6]1(=[O:30])=[O:29])(C)(C)C.FC(F)(F)C(O)=O>>[O:30]=[S:6]1(=[O:29])[CH:7]([C:11]2[CH:28]=[CH:27][C:14]([CH2:15][C:16]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[CH2:8][C:9](=[O:10])[NH:5]1
Reactant: CCOC(=O)C1(Cc2ccc(C3CC(=O)N(C(C)(C)C)S3(=O)=O)cc2)CCC(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(Cc2ccc(C3CC(=O)NS3(=O)=O)cc2)CCC(=O)N1
Temperature: 130 °C
Yield: 84.3 %

Procedure:
Ethyl 2-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)benzyl]-5-oxopyrrolidine-2-carboxylate (34 mg, 0.078 mmol) was stirred in trifluoroacetic acid (3.0 mL, 40.0 mmol) in a small microwave tube and heated to 130° C. for 60 seconds. Trifluoroacetic acid was evaporated and the residue was purified by preparative LCMS to give the desired compound as a white solid (25 mg, 84%). 1H-NMR (400 MHz, CD3OD): δ 7.45 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.17 (t, J=8.9 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.30 (m, 2H), 3.20 (d, J=13.6 Hz, 1H), 3.10 (d, J=13.6 Hz, 1H), 2.38 (m, 1H), 2.21 (m, 2H), 1.95 (m, 1H), 1.23 (t, J=7.0 Hz, 3H); LCMS found for C17H21N2O6S (M+H)+: m/z=381.
Reaction SMILES: C=O.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CO.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:36][N:6]1[CH2:7][CH2:8][N:3]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[CH2:4][CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5)cc4)CC3)C2)c2ccccc21
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)CC1
Reaction time: 1 h

Procedure:
Formaldehyde (10.0 mg, 0.000333 mol) was added to a solution of (1R)-1′-{[1-(4-piperazin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (0.13 g, 0.00032 mol, example 421, step 1) in methanol (1.0 mL, 0.025 mol) followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol), and the mixture was stirred for 1 h. The crude product was purified by prep-HPLC. LC-MS: 432.3 (M+H)+
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCOC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(Cl)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 62.1 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (86.35 mg, 0.2553 mmol), 4-Chlorobenzaldehyde (39.5 mg, 0.281 mmol) and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 72.70 mg (63%) of the title compound. (300 MHz, DMSO-d6) 13.39 (s, 1H), 8.14 (d, J=9 Hz, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.63 (d, J=9 Hz, 2H), 7.21 (m, 2H), 6.41 (m, 1H), 6.37 (m, 1H), 5.21 (t, J=17 Hz, 9 Hz, 1H), 2.89 (s, 1H), 2.77 (s, 1H), 2.62 (d, J=9 Hz, 1H), 2.23 (d, J=9 Hz, 1H), 1.38 (d, J=9 Hz, 1H). MS=458 (M+H), HPLC: 2.77 min. (G Method)