Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(C2CCNCC2)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCC(c2cccc(Br)c2)CC1
Temperature: 25 °C

Procedure:
4-(3-Bromo-phenyl)-piperidine (1.2 g, 4.8 mmol) and 2-bromoethanol (0.72 mL, 10 mmol) were diluted with DMF (20 mL) and treated with potassium carbonate (2.7 g, 20 mmol). These were stirred at ambient temperature for 18 then poured onto water and extracted with ethyl acetate. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil (0.6 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:18])=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2sccc2c1
Reactant: O=Cc1ccccc1
Product: Cc1ccc2sc(C(O)c3ccccc3)cc2c1

Procedure:
Using general procedure B, 5-methyl-benzo[b]thiophene was reacted with benzaldehyde to give (5-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol as a colorless solid. MS: 237.1 ([M+H—H2O]+).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[Cl-].[NH4+]>CO.O.[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c(Br)c1Nc1ccccn1
Yield: 75.1 %

Procedure:
(2-Bromo-3-fluoro-6-nitro-phenyl)-pyridin-2-yl-amine (3.68 g, 11.8 mmol), iron powder (2.63 g, 47.2 mmol), and ammonium chloride (3.63 g, 70.7 mmol) in methanol (40 mL) and water (15 mL) were heated at 90° C. for 1.5 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to yield the title compound as a white solid (2.5 g, 75%). 1H NMR 400 MHz δ (CDCl3): 8.23-8.17 (1H, m), 7.48 (1H, ddd, J=8.4, 7.3, 1.9 Hz), 6.94 (1H, dd, J=8.8, 7.9 Hz), 6.77 (1H, ddd, J=7.2, 5.0, 1.0 Hz), 6.73 (1H, dd, J=8.8, 5.0 Hz), 6.31 (1H, dt, J=8.3, 1.0 Hz), 6.10 (1H, br s), 3.94 (2H, br s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.BrBr.BrC1C=CC2N=C(N)SC=2C=1>CC#N.C(O)(=O)C>[Br:1][C:2]1[C:3]2[S:10][C:9]([NH2:11])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1cccc(Br)c1
Agent: BrBr
Agent: Nc1nc2ccc(Br)cc2s1
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1nc2cccc(Br)c2s1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
1-(3-Bromophenyl)-2-thiourea (Oakwood Products, Inc., West Columbia, S.C.; 2.479 g, 10.73 mmol) was suspended in MeCN (200 mL) and cooled in an ice water bath under nitrogen. Then, a solution of bromine (1.1 mL, 21 mmol) in acetic acid (10 mL) was added dropwise over 15 minutes. The reaction was stirred while being cooled in an ice water bath for 30 minutes, then allowed to warm to RT while stirring over the weekend. The resulting precipitate was filtered and the solid was washed with Et2O to afford the mixture (2.5 g, 100% yield) of 7-bromobenzo[d]thiazol-2-amine and 6-bromobenzo[d]thiazol-2-amine in a 1:2 ratio. MS (ESI pos. ion) m/z: 229 (MH+, 79Br), 231 (MH+, 81Br). Calculated exact mass for C7H5BrN2S: 228 (79Br), 230 (81Br).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:10]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.N>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([I:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(N)ncc1Br
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1c(Br)cnc(N)c1I
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
5-Bromo-4-methylpyridine-2-amine (3.1 g) was dissolved in acetic acid (20 ml). N-Iodosuccinimide (3.8 g) and trifluoroacetic acid (0.2 ml) were added and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into ice water and neutralized with 28% aqueous ammonia. Then, the precipitated solid was collected by filtration, washed with water and dried to give the title compound (4.9 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]([N:4]2[C:5]3[CH:10]=[C:9]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)[CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:31])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=C1CCC(c2ccc3c(c2)NCCO3)=NN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCOc3ccc(C4=NNC(=O)CC4)cc32)cc1OC

Procedure:
6-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one was dissolved in methylene chloride and 1.1 equivalent of triethylamine. 1.1 equivalent of 3,4-dimethoxybenzoylchloride was added and the mixture heated at reflux for four hours. The solution was washed with sodium bicarbonate solution and then evaporated to dryness. The residue was chromatographed on silica gel eluting with 1:1 ethyl acetate:ethyl ether. The title compound was collected as white needles, mp 207°-208° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C(=O)C(CO[S:47]([CH3:50])(=O)=O)=CC(C2C=CC(SC)=CC=2)=N1)C(C)C.CN1CCNCC1>>[CH2:29]([N:16]1[C:15](=[O:33])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[C:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:47][CH3:50])=[CH:23][CH:22]=2)=[N:17]1)[CH:30]([CH3:32])[CH3:31]
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: CSc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C)CC3)c2C)cc1
Yield: 68.3 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.3%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].[I:16]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([I:16])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(Cl)nc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To solution of 6-chloro-pyridin-3-ol (112 g, 868 mmol) in THF (800 mL)/Water (800 mL) was added sodium carbonate (92.0 g, 1.736 mol) and iodine (244.2 g, 1.04 mol). The reaction mixture was stirred rt 4 h. The aqueous layer containing product was separated and washed with hexane (400 mL×2). The aqueous layer was neutralized to pH=7 with HCl and then extracted EtOAc (500 mL×4). The combined organic layers were dried over Na2SO4, and filtered. The filtrate was concentrated to the crude product, which was washed with EtOAc to afford 163 g of 6-chloro-2-iodopyridin-3-ol, yield: 75%. 1H NMR (DMSO, 400 MHz): δ11.13 (s, 1H, OH), 7.31 (dd, J=8.4, 12.8 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[CH:4][N:3]=1.[F-:16].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: CCCOc1cnc(Cl)c2ccccc12
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCOc1cnc(F)c2ccccc12
Temperature: 140 °C
Yield: 68.8 %

Procedure:
To a solution of 1-chloro-4-propoxyisoquinoline (1.1 g, 4.96 mmol) in DMSO (6 mL), added CsF (1.508 g, 9.92 mmol) and heated to 140° C. for 6 h. The reaction was diluted with ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-25% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 700 mg of the desired product 1-fluoro-4-propoxyisoquinoline as a white solid. MS: MS m/z 206.17 (M++1).
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]([N:21]([CH3:30])[CH:22](C2C=CC=CC=2)C)([C:15]2C=CC=CC=2)[PH2]=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]3[C:47]([CH3:70])=[N:48][N:49]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:50]=3)=[CH:44][CH:45]=2)=O)=[CH:34][CH:33]=1>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]3[C:47]([CH3:70])=[N:48][N:49]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:50]=3)=[CH:44][CH:45]=2)=[CH:30][N:21]([CH3:22])[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:15])=[CH:34][CH:33]=1
Reactant: CC(c1ccccc1)N(C)C([PH2]=O)(c1ccccc1)c1ccccc1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=O)c2ccc(Cl)cc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=CN(C)C(C)c2ccccc2)c2ccc(Cl)cc2)cn1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.47 ml, 0.76 mmol, 1.6M in Hexanes) was added dropwise to a solution of (R) (Diphenyl-phosphinoylmethyl)-methyl-(1-phenyl-ethyl)-amine* (0.18 g, 0.51 mmol) in dry tetrahydrofuran (9 ml) at −15° C. After 15 minutes a solution of (4-Chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone (0.14 g, 0.25 mmol) in tetrahydrofuran (0.9 ml) was added and the reaction mixture was stirred for a further 30 minutes at −15° C. before warming to room temperature over 1 hour. The reaction mixture was quenched with water, extracted with diethyl ether, organic extracts were combined, dried (MgSO4) and concentrated to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[F:27][C:28]1([F:32])[CH2:31][N:30]([C:19]([C:18]([NH:17][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:14][CH2:13]3)[N:8]=2)=[O:16])([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:21])[CH2:29]1
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Reactant: FC1(F)CNC1
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e=422.0 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:12][C:13]([C@@:15]1([CH:30]([CH3:32])[CH3:31])[O:19][N:18]=[C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)[CH2:16]1)=[O:14])[C:9]([OH:11])=O)(C)(C)C.[CH:34]([Mg]Br)=[CH2:35]>>[CH:30]([C@:15]1([C:13]([NH:12][C@H:8]([C:9](=[O:11])[CH:34]=[CH2:35])[CH2:7][C:6]([OH:5])=[O:33])=[O:14])[O:19][N:18]=[C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)[CH2:16]1)([CH3:31])[CH3:32]
Reactant: CC(C)[C@@]1(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)CC(c2nccc3ccccc23)=NO1
Reactant: C=C[Mg]Br
Product: C=CC(=O)[C@H](CC(=O)O)NC(=O)[C@]1(C(C)C)CC(c2nccc3ccccc23)=NO1

Procedure:
Weinreb amide derivative of (2S)-4-(tert-butoxy)-2-({[(5R)-5-isopropyl-3-(1-isoquinolinyl)-4,5-dihydro-5-isoxazolyl]carbonyl}amino)-4-oxobutanoic acid (condensed derivative with N,O-dimethylhydroxylamine) and vinyl magnesium bromide were reacted, and the resulting compound was reacted according to the same procedure as Example 2 to give the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]([S:13][CH3:14])[N:6]=1.C[O:17][C:18](=O)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[O:20][C:19]1[C:18](=[O:17])[N:4]([CH2:3][C@H:2]([OH:1])[CH3:15])[C:5]2[N:6]=[C:7]([S:13][CH3:14])[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)COc1ccc(F)cc1F
Reactant: CSc1ncc(C=O)c(NC[C@@H](C)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Oc3ccc(F)cc3F)c(=O)n(C[C@@H](C)O)c2n1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
To a mixture of 4-((R)-2-hydroxy-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (17.7 g, 78 mmol) and (2,4-difluorophenoxy)acetic acid methyl ester (31.6 g, 156 mmol) in anhydrous dimethyl formamide (300 mL) was added potassium carbonate (30 g, 218 mmol). The reaction mixture was heated to 60° C. and after 18 hours, reaction mixture was cooled and DMF was distilled off. Residue suspended in water (300 mL) and extracted with dichloromethane, washed with brine and dried over magnesium sulfate. Filtered and concentrated under vacuum to give 29.5 g crude material which was chromatographed on silica gel column eluding with 1% methanol in dichloromethane to give 17.5 g 6-(2,4-difluorophenoxy)-8-((R)-2-hydroxypropyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec M+1=274).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1cccc(-c2cnc3[nH]cc(I)c3c2)c1)N1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
A mixture of (3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (600 mg, 1.38 mmol), p-toluenesulfonyl chloride (528 mg, 2.77 mmol), potassium hydroxide (50% w/v in water, 0.387 mL, 3.45 mmol) and tetrabutylammonium hydroxide (40% w/v in water, 0.448 mL, 0.69 mmol) in toluene (5 mL) was stirred at room temperature for 15 hours. Water was added to the mixture and the aqueous mixture was extracted by ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (600 mg, 74% yield) as yellow solids. MS: m/z 588.1 (M+H+).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=3[CH3:33])[C@H:15]2[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:32][C:26]1[C:25]([CH3:33])=[C:24]([C:14]2[C@@H:15]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-((3S,3aR,4S)-4-(tert-butyldimethylsilyloxy)-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (120 mg, 0.245 mmol) in THF (2 mL) at 0° C. was added tetrabutylammonium fluoride (0.49 mL, 0.490 mmol, 1M solution in THF) and the reaction mixture was stirred at room temperature for 3 h. Once the starting material had disappeared (monitored by TLC), it was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification of crude by column chromatography over silica gel using 30% EtOAc in hexane provided the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu][C:12]#[N:13].Cl.O>CN(C=O)C>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:13]
Reactant: N#C[Cu]
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)c(C=O)c1
Temperature: 190 °C
Reaction time: 5 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190 ° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65 ° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10% sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C@H:8]2[OH:11])=[CH:4][CH:3]=1.C(OC(=O)CCC)=C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O[C@@H]1C[C@H](c2ccccc2)c2ccc(Cl)cc21
Agent: C=COC(=O)CCC
Solvent: Cc1ccccc1
Product: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21
Reaction time: 24 h

Procedure:
Compound V (5 g, 20.4 mmol) is dissolved in 150 ml anhydrous toluene. 0.5 g Novozym 435 (Candida Antarctica lipase B) (Novozymes A/S, Fluka Cat.-No. 73940) is added followed by vinylbutyrate (13 ml, 102.2 mmol). The mixture is stirred using mechanical stirrer at 21° C. After 1 day, an additional 0.5 g Novozym 435 is added. After 4 days at a conversion of 54%, the mixture is filtered and concentrated in vacuo to obtain an oil containing a mixture of (1R, 3R)-cis-6-chloro-3-phenylindan-1-ol-butyrate ester and desired compound Va with an enantiomeric excess of 99.2% (99.6% compound Va and 0.4% (1R, 3R)-cis-6-chloro-3-phenylindan-1-ol).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:29]=1[C:30]#[N:31]>>[C:30]([C:29]1[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:28]=1[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=2[CH:13]=1)#[N:31]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1ccc(F)c(C#N)c1
Product: Cc1ccc(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C#N)c1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-methyl-benzonitrile following a procedure analogous to that described for Intermediate 12. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.12 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[CH2:13]([O:15][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH3:36])[CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])[CH3:14].C(N(CC)CC)C>ClCCl>[C:8]([O:7][C:1]([CH2:36][NH:35][CH2:34][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][CH:16]([O:15][CH2:13][CH3:14])[C:17]([O:19][CH3:20])=[O:18])=[CH:23][CH:24]=2)[CH:33]=[CH:32][CH:31]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A solution of 0.4 g (1.9 mmol) of di-tert-butyl carbonate in 5 ml of dichloromethane is added dropwise to a solution of 0.6 g (1.9 mmol) of methyl 2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate and 0.25 ml (1.9 mmol) of triethylamine in 10 ml of dichloromethane. After stirring at room temperature for 48 hours, the medium is washed with water, extracted with dichloromethane, dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 0.78 g of methyl 3-{3′-[(tert-butoxycarbonylmethylamino)-methyl]biphenyl-4-yl}-2-ethoxypropionate is obtained in a yield of 85%.
Reaction SMILES: [C:1]([NH:4][NH:5][CH:6]1[CH:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]2=[N:7]1)(=O)[CH3:2].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:2][C:1]1[N:7]2[C:8]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:12][C:6]2=[N:5][N:4]=1
Reactant: CC(=O)NNC1C=NC(c2ccccc2)=c2cc(Cl)ccc2=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 92.5 °C
Reaction time: 4.5 h
Yield: 80 %

Procedure:
2-(2-acetyl hydrazino)-7-chloro-5-phenyl-2H-1,4 benzodiazepine (117.5 g; 0.36 mole) and toluene (11.75 mole.) were added to a RB flask. 0.94 mole of toluene was distilled out at 110-112° C. The reaction mixture was cooled to 90-95° C. and charged with p-toluene sulphonic acid (0.0012 mole). The reaction mixture was then refluxed at 105-110° C. for 10-12 hrs with a Dean-Stark apparatus for water removal. At the end of the reaction (as indicated by TLC), reaction mixture was cooled to 25-30° C. The reaction mass was then further cooled to 10-15° C. and stirred at same temperature for 4-5 hrs. The solids precipitated were filtered and washed with cold toluene to obtain crude 8-chloro-1-methyl-6-phenyl-4H-s-trizolo[4 3-I][1,4] benzodiazepine (alprazolam). The crude alprazolam was purified from isopropanol to obtain 80% yield of pure alprazolam.