Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[CH2:15][CH2:14][C@@:13]23[C:16]4[C:22]5[CH2:23][C@@H:3]1[C@@H:4]2[CH2:5][CH2:6][C:7]1([C@@H:12]3[O:18][C:17]=4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=5)[O:11][CH2:10][CH2:9][O:8]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC1(C)CC(=O)CC(=O)C1.CO.Cl>CN(C)C=O>[O:8]1[CH2:9][CH2:10][O:11][C:7]21[CH2:6][CH2:5][C@@H:4]1[C@@:13]34[C:16]5[C:22](=[CH:21][CH:20]=[C:19]([C:24]#[N:25])[C:17]=5[O:18][C@@H:12]23)[CH2:23][C@H:3]1[NH:2][CH2:15][CH2:14]4
Reactant: CN1CC[C@]23c4c5ccc(C#N)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)NCC[C@@]351)OCCO4
Temperature: 55 °C
Yield: 81 %

Procedure:
To a suspension of (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (5.0 g, 17.8 mmol) in dimethylformamide (50 mL) was added diisopropyl azodicarboxylate (5.4 mL, 27.5 mmol). The reaction was heated to 55° C. for 3 hours until the starting material was consumed. To the reaction was added dimedone (5.8 g, 41.4 mmol) and methanol (1.75 mL, 54.8 mmol) and the reaction heated to 60° C. for 3 hours. The reaction was allowed to cool to room temperature and poured into 0.5 M HCl(aq) (50 mL). The aqueous phase was washed with diethyl ether: ethyl acetate (3:1). The organic phase was back extracted with 0.5 M HCl(aq) and acidic phases combined before basifying with 2M NaOH until pH9. The aqueous phase was extracted with ethyl acetate (×3). The combined organic phases were washed with water/brine (×3) before drying over MgSO4 and concentrating under reduced pressure. The residue was purified by silica chromatography (5% methanol in dichloromethane to 5% NH3/methanol in dichloromethane) to give (4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile as a pale yellow solid (3.90 g, 95% pure LCMS, 81% yield); [M+H]+325.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:2]2[CH:7]=[CH:6][C:5]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)(=[O:26])=[O:25])=[CH:21][CH:22]=4)[CH:17]=[CH:16][N:15]=3)=[C:4]([O:11][CH3:12])[CH:3]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1-c1ccc(-c2nccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
A solution of Pd(Amphos)2Cl2 (0.442 g, 0.624 mmol), (4-chloro-2-methoxyphenyl)boronic acid (1.278 g, 6.86 mmol), 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (2.000 g, 6.24 mmol), and potassium phosphate (5.29 g, 24.94 mmol) in 30 mL dioxane/12 mL water was heated to 110° C. for 2 hours. LC/MS showed product, so the reaction mixture was allowed to cool to room temperature. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane) (6.24 ml, 24.94 mmol). After stirring for 10 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4′-chloro-2′,3-dimethoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.073 g, 0.137 mmol, 2.197% yield). 1H NMR (MeCN-d3) δ: 8.69 (m, 1H), 8.62 (s, 1H), 8.44-8.52 (m, 1H), 8.21 (d, J=6.4 Hz, 1H), 7.89-7.99 (m, 2H), 7.81 (d, J=9.0 Hz, 1H), 7.42 (m, 1H), 7.32-7.39 (m, 1H), 7.29 (s, 1H), 7.24 (m, 1H), 7.16 (d, 1H), 7.03-7.12 (m, 2H), 3.84-3.88 (m, 3H), 3.64-3.67 (m, 3H); (M+H)+=533.0.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Br[CH2:19][CH2:20][CH2:21][CH2:22]Cl.C([O-])([O-])=O.[K+].[K+].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CCO.CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: ClCCCCBr
Reactant: C1CCNC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCCN3CCCC3)cc2)CCOCC1
Yield: 18.3 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.5 g, 6.38 mmol), 1-bromo-4-chlorobutane (1.5 ml, 12.77 mmol), DMF (20 ml) and K2CO3 (3.5 g, 25.53 mmol) were reacted together according to general procedure B. Purification of a fraction of the crude (900 mg) by chromatography on alumina, eluant ethyl acetate:heptanes (12:88) provided a mixture of bromo and chloro phenoxy ether (220 mg) which was used in the next stage. The purified mixture (220 mg, 0.68 mmol) and pyrrolidine (0.17 ml, 2.03 mmol) were refluxed in EtOH (3 ml, 15 vol) overnight. The reaction was concentrated in vacuo and partitioned between 2M NaOH (10 ml) and ethyl acetate (10 ml). The aqueous was extracted with ethyl acetate (3×5 mL). The combined ethyl acetate layers were washed with brine (3×5 ml), dired over MgSO4, filtered, washed with ethyl acetate and concentrated in vacuo. Purification by chromatography on silica, eluant 95:3:2 (DCM:MeOH:NH3) followed by a second column eluting with DCM:MeOH:NH3 (96.5:3:0.5), gave the title compound as a colourless oil (134 mg, 55%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 3.97 (t, 2H), 3.75 (dt, 2H), 3.59-3.50 (m, 2H), 2.57-2.45 (m, 6H), 2.40 (s, 2H), 2.14-2.05 (m, 2H), 1.96 (s, 6H), 1.92-1.65 (m, 10H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][CH:10]([OH:13])[CH2:11][CH3:12]>>[CH3:9][C:10]([OH:13])([CH2:11][CH3:12])[CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCC(C)O
Product: CCC(C)(O)CCc1ccccc1

Procedure:
A solution of styrene in 2-butanol (20% by weight, 100 g/h) was pumped continuously at an average temperature of 390° C. in the reactor through the laboratory plant. The conversion of styrene was 84.0% and, in the steady state, 14.7 g/h of 3-methyl-1-phenyl-3-pentanol were obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C.Cl>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CCCc1ccc(Br)cc1
Agent: [Cu]I
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCc1ccc(C#C[Si](C)(C)C)cc1
Yield: 87.1 %

Procedure:
To 15.0 g (75.4 mmol) of 1-n-propyl-4-bromobenzene were added 8.8 g (89.8 mmol) of trimethylsilylacetylene and 100 ml of triethylamine (NEt3), and the reaction system was purged with argon. Next were added 81 mg (0.4 mmol) of copper (I) iodide (CuI), 324 mg (1.2 mmol) of triphenylphosphine, and 162 mg of dichlorobistriphenylphosphine palladium (II) [PdCl2(PPh3)2] to the reaction system, and the mixture was subjected to reaction for 24 hours with heating and refluxing. After completion of the reaction, the reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. After the resultant water-insoluble oil was extracted with hexane, the hexane phase was washed with water. By removing hexane from the hexane phase, 14.2 g (65.7 mmol) of 1-(4-n-propylphenyl)-2-trimethylsilylacetylene was obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH3:39])[CH:32]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[ClH:37].[F:27][C:25]([F:26])([F:28])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH3:39])[CH:32]=1)=[O:29]
Reactant: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1Cl
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COc1cc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1Cl
Product: Cl
Yield: 198 %

Procedure:
A solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(4-chloro-3-methoxybenzyl)piperazine (2.23 g) and 1-chloroethyl chloroformate (0.61 ml) in 1,2-dichloroethane (10 ml) was stirred under reflux for 15 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting syrup was dissolved into methanol (10 ml) and the solution was stirred under reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the resulting powder was collected by filtration to give a yellow powder of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-methoxybenzyl)piperazine hydrochloride (2.00 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O-:39])=[O:38])[CH2:21][CH:20]2[CH2:40][OH:41])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](=[O:45])([O-])[O-].[Li+].[Li+].C(Cl)(Cl)=O.[NH2:52][CH2:53][CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]1>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:38])[CH2:21][CH:20]2[CH2:40][O:41][C:42](=[O:45])[NH:52][CH2:53][CH2:54][CH2:55][N:56]2[CH2:57][CH2:58][N:59]([CH3:62])[CH2:60][CH2:61]2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN(CCCN)CC1
Reactant: O=C([O-])N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C(Cl)Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCN(CCCNC(=O)OCC2CN(C(=O)OC(C)(C)C)CC(OCc3ccc4ccccc4c3)C2c2ccc(OCCCOCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 90 mg (0.15 mmol) of tert-butyl 3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148 (h)] and 60 mg (0.75 mmol) of lithium carbonate in 10 ml of dry tetrahydrofuran was cooled to 0° C. A solution of 0.90 ml (1.6 mmol) of phosgene in toluene (1.93N) was added dropwise thereto while cooling with ice. The mixture was stirred at room temperature overnight in order complete the reaction. The reaction mixture was evaporated under reduced pressure in order to remove the excess phosgene and the crude chloroformate obtained was taken up in 10 ml of tetrahydrofuran. This mixture was treated with 58 mg (0.38 mmol) of 1-(3-aminopropyl)-4-methylpiperizine and stirred at room temperature for 3 hours. For the working-up, the reaction mixture was diluted with 40 ml of methylene chloride and then extracted with 20 ml of water. The organic phase was dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 85 mg (73% of theory) of tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-propylcarbamoyloxymethyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 795 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34](F)[C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:55][C:50]2C=CC=CC1=2)=[N+](C)C)C.[F:57][P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C1COCC1>[CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([F:57])=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:55][CH3:50])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2c(C)ccc(C(=O)NC)c2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and methylamine (41.5 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9.6 mg, 31.5%). LC-MS m/z 553 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([OH:18])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(Cl)c(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.8 %

Procedure:
To a solution of Example 95 (0.055 g, 0.1012 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 0.5 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as pale green solid (0.025 g, 86% yield). MP: 134-136° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.50 (s, 1H), 8.18 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.87 (t, J=7.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.29 (br s, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.07-6.93 (m, 4H), 6.07 (q, J=6.9 Hz, 1H), 1.90 (d, J=7.0 Hz, 3H). Mass: 527.76 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH:30]=O)=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:8])=[O:7])=[CH:2]1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH2:30][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:8])=[O:7])=[CH:2]1
Reactant: C1CCNC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Yield: 70.5 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.0650 g, 0.114 mmol) was dissolved in acetonitrile (5.0 mL), and the solution was treated with pyrrolidine (0.191 mL, 2.29 mmol), acetic acid (0.131 mL, 2.29 mmol) and sodium triacetoxyborohydride (0.0730 g, 0.343 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15, 80/20) to obtain 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.0501 g, 70%).
Reaction SMILES: [F:1][C:2]([F:36])([CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[OH:27])=[CH:7][CH:6]=1.Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=2[CH:54]=1>>[F:36][C:2]([F:1])([CH2:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=3[CH:54]=2)=[CH:7][CH:6]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(OCC(F)(F)COc3ccccc3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCC(F)(F)COc4ccccc4)cc3)cc21

Procedure:
Analogously to Method D, 0.260 g of benzyl 4-[4-(2,2-difluoro-3-phenoxypropoxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 0.185 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellow oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=5.67.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH:6]([OH:8])[CH3:7].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C)C=O>[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH:6]([CH3:7])[O:8][CH2:13][CH:12]=[CH2:11]
Reactant: COC(OC)C(C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)C(OC)OC
Reaction time: 0.25 h

Procedure:
60% sodium hydride (992 mg) was added to a solution of 1,1-dimethoxy-propan-2-ol (2.49 g) in dimethylformamide (50 mL) at 0° C., followed by stirring for 15 minutes. Allyl bromide (1.96 mL) was added at the same temperature, followed by stirring for 15 minutes. Ice was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (3.46 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl.Cl.CCCCCC>N1C=CC=CC=1.C1C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][S:10][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Fc1ccccc1CCl
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccccc2F)c(=O)o1
Temperature: 90 °C
Yield: 46 %

Procedure:
4-Hydroxy-3-mercapto-6-methyl-2-pyrone (49.5 g., 0.313 mole) and o-fluorobenzyl chloride (45.3 g., 0.313 mole) were dissolved in pyridine (250 ml.). The temperature rose from 20° to 43°C. The solution was heated at 90°C. for two hours, cooled and poured over ice and concd. hydrochloric acid (500 ml.). This mixture was extracted with methylene chloride. The extract was dried (MgSO4) and evaporated to dryness, leaving an oily residue (80 g.) which is dissolved in hot benzene. Hexane was added to this hot benzene solution and an oil separated. The solution was decanted off. This was repeated until a solid separated. The mixture was cooled and filtered, giving 38.0 g. (46 percent) of the desired product. Recrystallization from benzene gave the pure product as a pale yellow solid, m.p. 123°-125°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][OH:21])[C:10]=2[CH2:9][CH:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21][S:32]([CH3:31])(=[O:34])=[O:33])[C:10]=2[CH2:9][CH:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:24]
Reactant: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 76.9 %

Procedure:
To a solution of 9-(2-hydroxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (49) (250 mg, 0.8 mmol) in dichloromethane (10 mL) was added pyridine (633 mg, 8.0 mmol, 0.6 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (367 mg, 3.2 mmol, 0.2 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×20 mL) and water (2×20 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% B, 10 g, 34 CV, 30 mL/min) then triturated with diethyl ether to afford 250 mg (80%) of methanesulfonic acid 2-(4-diethylcarbamoyl-2-methyl-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound II) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 12.9, 13.0, 15.2, 22.0, 29.7, 30.2, 36.7, 36.8, 40.8, 41.6, 42.0, 67.8, 108.6, 109.5, 118.6, 119.6, 121.2, 126.4, 136.2, 136.4, 173.7.
Reaction SMILES: [C:1]([CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])([O:3]C)=[O:2].[C:11]([CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1)([O:13]C)=[O:12]>>[C:1]([CH2:5][CH:6]([CH3:10])[C:7]([N:16]1[C@H:15]([C:11]([OH:13])=[O:12])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:8])([OH:3])=[O:2]
Reactant: COC(=O)C1Cc2ccccc2CN1
Reactant: COC(=O)CC(C)C(=O)Cl
Product: CC(CC(=O)O)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O

Procedure:
Using the method described in example 8, beginning from 3-carbomethoxy 2-(RS) methylpropionic chloride and 3-(RS) carbomethoxy 1,2,3,4-tetrahydro isoquinoline, the following are obtained successively:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:27])([OH:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C@:11]3([CH3:27])[O:26][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:10]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: C[C@](O)(CN1CCN(c2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(c3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.4 %

Procedure:
(S)-1-(2-Chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-chlorophenyl)piperazin-1-yl]propan-2-ol prepared in Example 370 (33.0 g, 79.7 mmol) was dissolved in DMF (300 ml). To the solution, sodium hydride (3.7 g, 91.6 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, ice-water and ethyl acetate were added, and the solution was vigorously stirred. The precipitates were filtered off, washed with water and ethyl acetate, and dried under reduced pressure to afford 23.2 g of a crude light yellow powder. The crude powder was combined with another crude powder synthesized in the same manner (50 g), and the mixture was purified by silica gel column chromatography (methylene chloride/ethyl acetate=50/1) and crystallized from methylene chloride-ethyl acetate to afford (S)-2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (45 g, yield 90%) as a white powder.