Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(OC(F)(F)F)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (76 mg, 80%), MS (ISP) m/z=379.5 [(M+H)+], mp 162° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=2[NH:12][C:11](=[S:31])[CH2:10][N:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=O)N2
Product: Cc1cc2c(cc1C)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-1,3-dihydro-7,8-dimethyl-2H-1,4-benzodiazepin-2-thione (Iw) was prepared by reacting 0.0006 moles of 5-(2-chlorophenyl)-1,3-dihydro-7,8-dimethyl-2H-1,4-benzodiazepin-2-one (Iw) with Lawesson's reagent in a manner analogous to Example 38.
Reaction SMILES: Cl.[C:2]([C:12]1[CH:29]=[CH:28][C:15]([CH2:16][NH:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1)#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH:30]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:35][CH2:36][C:37]([N:17]([CH2:16][C:15]2[CH:14]=[CH:13][C:12]([C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:29][CH:28]=2)[C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:38])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCCCCCCC#Cc1ccc(CNc2cccc(C(=O)OC)c2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Agent: Cl
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)CCC2CCCC2)c2cccc(C(=O)OC)c2)cc1

Procedure:
The titled compound was prepared following the procedure G using methyl 3-[(4-dec-1-yn-1-ylbenzyl)amino]benzoate hydrochloride and 3-cyclopentylpropanoyl chloride as a pale yellow oil (76%). 1H NMR (CDCl3, 300 MHz) δ 7.99 (d, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.38 (m, 1H), 7.29 (d, J=8.3 Hz, 2H), 7.09 (m, 3H), 4.88 (s, 2H), 3.93 (s, 3H), 2.39 (t, J=7.0 Hz, 2H), 2.06 (m, 2H), 1.61-1.30 (m, 21H), 0.95 (m, 2H), 0.89 (t, J=6.8 Hz, 3H). M+ (ESI): 502.4. HPLC, Rt: 6.32 min (Purity: 99.9%).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.Cl[C:18]1[N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=1.FC(F)(F)C(O)=O>O1CCCC1.ClCCl>[CH3:31][N:19]1[C:20](=[O:30])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[N:23]=[C:18]1[O:3][CH:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a solution of sodium hydride (60 wt % in mineral oil, 0.772 g, 19.3 mmol) in tetrahydrofuran (92 ml) was added tert-butyl 4-hydroxy-piperidine-1-carboxylate (3.70 g, 18.4 mmol) at 0° C. The mixture was stirred at room temperature for one hour, then 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (4.09 g, 18.4 mmol) was added. The mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved into dichloromethane (37 ml), and trifluoroacetic acid (41.9 g, 368 mmol) was added to the solution. The mixture was stirred at room temperature for 5 hours. After concentration under reduced pressure, the residue was dissolved into water. The aqueous solution was washed with ethyl acetate and basified with potassium carbonate. Extraction with chloroform was performed three times. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one as a pale yellow solid (2.48 g, 8.63 mmol, 47%). This compound was used for the next reaction without further purification.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[C:29]([F:30])=[CH:28][C:10]([O:11][C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:27])=[C:9]([O:31]C)[CH:8]=1)[CH3:6].O>ClCCl>[CH2:5]([C:7]1[C:29]([F:30])=[CH:28][C:10]([O:11][C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:27])=[C:9]([OH:31])[CH:8]=1)[CH3:6]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A commercial solution of boron tribromide (1N in DCM, 3.5 mL, 3.46 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoy]piperazin-2-one (which may be prepared in accordance with the experimental described in Example 5, step 1; 500 mg, 1.28 mmol) in dichloromethane (4.3 mL) placed under argon at −30° C. The reaction mixture was stirred at room temperature for 36 hours then diluted by addition of dichloromethane (20 mL) and water (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/acetone (80:20) as eluent. The title product was obtained as a beige solid (440 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:36]
Reactant: C[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.44 mmol), (S)-2-aminopropan-1-ol (0.10 ml, 1.31 mmol), HBTU (331 mg, 0.87 mmol), and HOBT (134 mg, 0.87 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.31 mL, 1.75 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 149 mg (66%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])([OH:6])[CH2:4]Cl.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[O:6][CH2:4]1
Reactant: OC(CCl)(CCl)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc(C2(CCl)CO2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To 1.7 l of toluene solution of 433 g of 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol was added 870 ml of 20% aqueous solution of potassium hydroxide. After the resulting liquid was stirred at room temperature for 3 hours, the organic layer was separated therefrom The aqueous layer was extracted twice with 1 l of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The resulting organic layer as filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was distilled under reduced pressure to give 184 g of the desired compound.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[C:36]1([CH2:44][NH2:45])[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:43][CH2:42][C:39]2[CH:40]=[CH:41][C:36]([CH2:44][NH:45][C:7]3[N:8]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]4[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]4)[OH:14])[N:10]=[C:5]([NH:4][CH2:3][CH:2]([CH:26]4[CH2:27][C:28]([CH3:35])([CH3:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH2:31]4)[OH:1])[N:6]=3)=[CH:37][CH:38]=2)[N:6]=1
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: NCc1ccc(CN)cc1
Solvent: Cc1ccccc1C
Product: CC1(C)CC(C(O)CNc2nc(NCc3ccc(CNc4nc(NCC(O)C5CC(C)(C)NC(C)(C)C5)nc(NCC(O)C5CC(C)(C)NC(C)(C)C5)n4)cc3)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 0 °C

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (15.4 g) and p-xylylenediamine (1.4 g) were dissolved in xylene (50 ml) and the solution was heated to reflux for 5 hours. The reaction mixture was poured into ice water. After saturation with potassium carbonate, the mixture was extracted with a mixture of benzene (300 ml) and chloroform (500 ml). The extract was dried over anhydrous potassium carbonate and benzene and chloroform were distilled off. The resulting residue was treated with silica gel column chromatography (eluent=ethyl acetate:triethylamine:ethanol=3:1:1) to yield crystals, which were recrystallized from cyclohexane to give the desired product with a melting point of 151°-156° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)O.C(O)(=O)C.[I:21]I>O>[I:21][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:8]
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Reactant: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(I)c(C)c1[N+](=O)[O-]
Temperature: 90 °C
Yield: 236.9 %

Procedure:
To 1,3-dimethyl-2-nitro-benzene (68.5 g, 453.2 mmol) is added sulfuric acid (27.2 mL, 510 mmol), acetic acid (543.8 mL, 9.49 mol), iodine (46 g, 181.3 mmol) and HIO4 (91.9 g, 403.3 mmol). The reaction is heated to 90° C. for 7 days. The reaction mixture is cooled to ambient temperature and water (500 mL) is added. The resulting solid is collected by filtration and washed with cold water. The solid is dried under reduced pressure at 45° C. overnight to afford the title compound as a yellow solid (119 g, 95%). 1H NMR (300.16 MHz, CDCl3): δ 7.80 (d, J=8.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 2.37 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)[CH2:4][CH2:3]1.[C:33]([C:35]1[O:39][C:38]([C:40](O)=[O:41])=[CH:37][CH:36]=1)#[N:34].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CCOC(C)=O.ClCCl>[C:33]([C:35]1[O:39][C:38]([C:40]([NH:14][C:13]2[CH:12]=[CH:11][C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19][CH2:18]3)=[CH:9][C:8]=2[N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[O:41])=[CH:37][CH:36]=1)#[N:34]
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: CC1CCN(c2cc(N3CCN(CCOC(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCN(CCOC(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 94.1 %

Procedure:
The procedure of Example 4, step (c) was followed using 156 mg (0.348 mmol) of carbonic acid tert-butyl ester 2-{4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazin-1-yl}-ethyl ester (as prepared in the previous step), 78 mg of 10% palladium on carbon (50% by weight water), 52.5 mg (383 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 50.1 μL (0.575 mmol) of oxalyl chloride, and 121 μL (0.696 mmol) of DIEA. Chromatography on a 10-g silica SPE column with 5-20% EtOAc-dichloromethane afforded 176 mg (94%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.60 (br s, 1H), 8.29 (d, 1H, J=8.9 Hz), 7.21, 7.24 (AB q, 2H, J=3.7 Hz), 6.79 (d, 1H, J=2.6 Hz), 6.71 (dd, 1H, J=8.9, 2.6 Hz), 4.23 (t, 2H, J=5.8 Hz), 3.16-3.19 (m, 4H), 2.97-3.00 (m, 2H), 2.67-2.75 (m, 8H), 1.82-1.84 (m, 4H), 1.50-1.65 (m, 1H), 1.46-1.58 (m, 2H, partially obscured by t-Bu peak), 1.49 (s, 9H), and 1.07 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C29H39N5O5, 538.3 (M+H) and 438.2 (M-BOC+2H), found 538.2, 438.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[C:23]([C:30](Cl)=[O:31])[N:24]2[CH3:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:5]([C@H:2]([NH:1][C:30]([C:23]1[N:24]([CH3:29])[C:25]2[C:21]([CH:22]=1)=[C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:3][OH:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:5]([C@H:2]([NH:1][C:30]([C:23]1[N:24]([CH3:29])[C:25]2[C:21]([CH:22]=1)=[C:20]([OH:19])[CH:28]=[CH:27][CH:26]=2)=[O:31])[CH2:3][OH:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: Cn1c(C(=O)Cl)cc2c(OCc3ccccc3)cccc21
Product: Cn1c(C(=O)N[C@H](CO)Cc2ccccc2)cc2c(O)cccc21
Product: Cn1c(C(=O)N[C@H](CO)Cc2ccccc2)cc2c(OCc3ccccc3)cccc21

Procedure:
From (S)-2-amino-3-phenylpropan-1-ol and 4-benzyloxy-1-methyl-1H-indole-2-carbonyl chloride the intermediate compound (S)-N-[1-benzyl-2-hydroxyethyl]-4-(benzyloxy)-1-methyl-1H-indole-2-carboxamide was prepared by a method analogous to that described in Example 23. MS ES (M++H)=415. Hydrogenation of this intermediate by a method analogous to that described in Example 9 gave the title compound. MS ES (M++H)=325.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([N:11]1[C:15]([C:16]([O:18][CH2:19]C)=[O:17])=[C:14]([C:21]([O:23][CH2:24]C)=[O:22])[N:13]=[C:12]1[CH2:26]Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO>[CH2:4]([N:11]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([C:21]([O:23][CH3:24])=[O:22])[N:13]=[C:12]1[CH2:26][O:2][CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccccc1
Reaction time: 13 h

Procedure:
492 mg of a 28% w/v solution of sodium methoxide in methanol were added to a solution of 655 mg of diethyl 1-benzyl-2-bromomethylimidazole-4,5-dicarboxylate [prepared as described in step (ii) above] in 7 ml of methanol, and the mixture was allowed to stand at room temperature for 13 hours. At the end of this time, 2.5 ml of 1N aqueous hydrochloric acid were added to the reaction solution, and the methanol was removed by distillation under reduced pressure. The concentrate was mixed with ethyl acetate and water and then shaken. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 391 mg of the title compound as a syrup.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[CH:50]([S:53](Cl)(=[O:55])=[O:54])([CH3:52])[CH3:51]>C(Cl)Cl>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([C@@H:11]2[CH2:12][N:8]([S:53]([CH:50]([CH3:52])[CH3:51])(=[O:55])=[O:54])[CH2:9][C@H:10]2[C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)=[CH:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41787.4 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and isopropylsulfonyl chloride (77 mg, 0.54 μmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes) to yield 1-[(3R,4R)-4-(1H-indol-3-yl)-1-(propane-2-sulfonyl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline as a white solid (101 mg, 50%). M.p.=100-115° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.85 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.94 (t, J=7.2 Hz, 1H), 6.86 (t, J=7.6 Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.07-3.95 (m, 6H), 3.55-3.46 (m, 3H), 2.84 (t, J=6.0 Hz, 2H), 2.05 (t, J=5.6 Hz, 2H), 1.32 (m, 6H). LCMS: m/e 448.13 [M+H].
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH:15]=[O:16])[CH2:12][CH:13]=[CH2:14])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][OH:16])[CH2:12][CH:13]=[CH2:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: C=CCC(C=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(CO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Sodium borohydride (2.2 g) was added in four portions, over 10 minutes, to an ice-cooled solution of 4-(3,4-dichlorophenyl)-4-formylbut-1-ene (13 g) (see Preparation 21) in ethanol (100 ml). The mixture was stirred for a further 30 minutes before removing the solvent under reduced pressure to give a residue. This was suspended in water (50 ml), cooled to 0° C. and the mixture acidified (pH<6) with 2N aqueous hydrochloric acid solution. The mixture was extracted three times with dichloromethane, the organic phases combined and the solvent removed under reduced pressure. Dichloromethane (200 ml) was then added, the mixture stirred and filtered and the solvent removed from the filtrate under reduced pressure to give an oil. This was chromatographed on silica gel eluting with dichloromethane to give 4-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (7 g) as a orange oil.
Reaction SMILES: Cl[CH:2]([C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[CH2:57][CH2:56]2)=[CH:51][CH:50]=1)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C@@H:10]1[CH2:15][C@H:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:12]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:11]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)(=O)C>C(Cl)Cl.C(O)(=O)C.[Zn]>[CH:55]1([C:52]2[CH:51]=[CH:50][C:49]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[O:9][C@@H:10]3[CH2:15][C@H:14]([CH2:16][O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:13]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:12]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:11]3[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:54][CH:53]=2)[CH2:56][CH2:57]1
Reactant: ClC(c1ccc(C2CC2)cc1)c1ccncc1O[C@@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1ccc(COC[C@H]2C[C@@H](Oc3cnccc3Cc3ccc(C4CC4)cc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
In a nitrogen stream, zinc (0.14 g, 2.14 mmol) was added to a solution of 4-[chloro-(4-cyclopropylphenyl)-methyl]-3-((1R,2S,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethyl-cyclohexyloxy)pyridine (0.22 g, 0.28 mmol) in methylene chloride (4.1 mL) and acetic acid (12.4 mL), and the mixture solution was stirred at room temperature for 14 hours. To the reaction mixture was added ethyl acetate and the mixture was washed with a saturated hydrogencarbonate aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:1)] to obtain the title product (0.14 g, 67%).
Reaction SMILES: CN(C=O)C.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:27]([O:26][C:24](=[O:25])[CH2:23][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)/C=C/c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)/C=C/c1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a 0.1 M DMF solution of ethyl (2E)-3-(1H-indol-2-yl) acrylate from Step 2 was added 1.4 equiv. of BrCH2CO2-t-Bu and 2.1 equiv. of Cs2CO3. The reaction mixture was stirred at 60° C. for 24 h, and was then diluted with an equal volume of acetone and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with EtOAc/Hex (1:2) to give the title compound (98%) as a syrup.