Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22]C(OC(C)(C)C)=O)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:32][C:2]([Cl:1])([Cl:33])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methylbutyrylamino)-propionyl]-hexahydropyridazine-3-carboxylic acid 2,2,2-trichloroethyl ester (316 mg, 0.59 mmol) in anhydrous dichloromethane (10 mL) was cooled to 0° C. under a nitrogen atmosphere before adding trimethylsilyl trifluoromethanesulfonate (160 μL, 0.885 mmol). The reaction mixture was stirred at 0° C. for 2 h before adding N,N-diisopropylethylamine (413 μl, 2.36 mmol) to afford (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloroethyl ester. The mixture was evaporated and the residue dissolved with (2R,3R)-3-methoxy-2-methyl-hept-6-enoic acid (162 mg, 0.94 mmol.) in acetonitrile (13 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (250 mg, 1.32 mmol) and 1-hydroxybenzotriazole (220 mg, 1.32 mmol) were added. The reaction was stirred at RT for 15 h then evaporated to give a yellow oil. The oil was purified by silica gel chromatography using ethyl acetate to give the title compound (425 mg, 77%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cu][C:15]#[N:16].CCCCCC.C(OCC)(=O)C>CN(C)C=O>[C:15]([C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]([CH3:12])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: COC(=O)c1c(C)ccc(F)c1I
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(C)ccc(F)c1C#N
Yield: 73 %

Procedure:
Methyl 3-fluoro-2-iodo-6-methylbenzoate (440 mg, 1.49 mmol) and copper(I) cyanide (200 mg, 2.24 mmol) were dissolved in N,N-dimethylformamide (5.5 mL) and the resulted solution was refluxed under nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (n-hexane/ethyl acetate: 7/3) afforded title compound (210 mg, 73% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CSC.B>O1CCCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1ccc(I)cc1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-iodobenzoic acid (22 g) in tetrahydrofuran (450 mL) was added borane dimethylsulfide complex (35.5 mL, 10M in tetrahydrofuran), and the solution was allowed to stir overnight. The reaction was quenched by addition of methanol, and the solvent was evaporated. The residue was dissolved in ethyl acetate and filtered. The solvent was evaporated to give a solid, which was recrystallized from ether to yield a white solid, which was chromatographed, eluting with ether, to give 4-iodobenzyl alcohol (15.1 g).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:66])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:66])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 67 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (38 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.52-7.48 (m, 2H), 7.42-7.31 (m, 5H), 7.14 (d, J=8.4 Hz, 2H), 4.37 (s, 3H), 3.27 (bs, 2H), 2.40-2.28 (m, 2H), 2.14-2.04 (m, 2H), 2.02-1.91 (m, 1H), 1.69-1.57 (m, 1H). LCMS (Method E): RT=3.42 min, [M+H]+=422.
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[N:7]([C:18]([O:20][CH:21](Cl)[CH3:22])=[O:19])[C:6]=2[CH:5]=[C:4]([O:24][CH3:25])[C:3]=1[OH:26].[C:27]([OH:30])(=[O:29])[CH3:28]>C(OCC)(=O)C>[C:27]([O:30][CH:21]([O:20][C:18]([N:7]1[C:6]2[CH:5]=[C:4]([O:24][CH3:25])[C:3]([OH:26])=[C:2]([Br:1])[C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)=[O:19])[CH3:22])(=[O:29])[CH3:28]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C(=O)OC(C)Cl
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C(=O)OC(C)OC(C)=O

Procedure:
A mixture of 4-bromo-10-(1-chloroethoxycarbonyl)-2,7-dimethoxy-3-hydroxy-10H-phenothiazine (1 g) and mercuric acetate (1.46 g) in glacial acetic acid (30 ml) was stirred and heated at 85° for 10 minutes. After cooling the mixture was diluted with ethyl acetate, washed with water, aqueous NaHCO3 solution, and brine, dried and evaporated. Flash chromatography on a column of silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, afforded the pure title product (599 mg) m.p.: 162°-164° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH:15](OCC)OCC.C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[Cl:12][C:11]1[C:2]2[N:3]([CH:14]=[CH:15][N:1]=2)[C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(CBr)OCC
Reactant: Nc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc2ccccc2n2ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 218.2 %

Procedure:
To a stirred suspension of 2-amino-3-chloroquinoxaline (25.5 g, 141.8 mmol) in water/THF 1:1 (500 mL), at rt was added 2-bromo-1,1-diethoxyethane (83.8 g, 425.4 mmol) in one portion. After stirring at rt for 1 h, the mixture was heated to reflux for 3 h under stirring and then stirred for an additional 15 h at rt. The pH value of the mixture was adjusted to pH 8 by addition of solid sodium carbonate and the mixture was subsequently extracted with ethyl acetate (3×500 mL) and the combined organic extracts were dried with sodium sulfate. Removal of the solvent yields 4-chloro-imidazo[1,2-a]quinoxaline as an orange-white solid (63 g, 93%): 1H-NMR (300 MHz, d6-DMS): δ=9.05 (d, 1H), 8.51 (dd, 1H), 8.1 (dd, 1H), 7.99 (d, 1H), 7.89 (td, 1H), 7.76 (td, 1H) ppm. UPLC-MS: RT=0.88 min; m/z 204.6 [MH+]; required MW=203.6.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=3[CH3:27])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cccc(CBr)c1C
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.4 g, 1.351 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-2,3-dimethylbenzene (0.323 g, 1.621 mmol) and potassium carbonate (0.560 g, 4.05 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.4 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3H) 2.37 (s, 3H) 2.53 (s, 3H) 2.98-3.14 (m, 4H) 3.66-3.93 (m, 4H) 5.24 (s, 2H) 6.24 (d, J=7.58 Hz, 1H) 6.53 (d, J=2.27 Hz, 1H) 6.89-7.00 (m, 1H) 7.06-7.17 (m, 2H); MS (ES+) m/e 414.1 [M+H]+
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[NH2:7][C:8]1[C:17]2=[N:18][N:19]([CH2:29][CH3:30])[C:20]([CH2:21][C:22]3([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>C(Cl)(Cl)Cl>[NH2:7][C:8]1[C:17]2=[N:18][N:19]([CH2:29][CH3:30])[C:20]([CH2:21][C:22]3([OH:28])[CH2:27][CH2:26][N:25]([C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH2:24][CH2:23]3)=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCN=C=O
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)N1CCC(O)(Cc2c3c(nn2CC)c(N)nc2ccccc23)CC1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
n-Propyl isocyanate (86 μL, 0.922 mmol) was added to a slurry of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-4-ol (0.300 g, 0.922 mmol) in chloroform (10 mL). After 16 hours, the solution was purified via automated flash chromatography eluting with a linear gradient of 2-25% CMA in chloroform. The residue was triturated in acetonitrile and isolated by filtration to provide 0.277 g of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]-4-hydroxy-N-propylpiperidine-1-carboxamide as a flocculent white solid, mp 208.5-210° C.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:22]([Mg]Br)=[CH2:23].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH:22]=[CH2:23]
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC1CCCCO1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)COC1CCCCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
A solution of 6,10-dimethyl-11-(2-tetrahydropyranyl) oxy-5,9-undecadien-2-one (80 mg, 0.27 mmol) in tetrahydrofuran (3 ml) was stirred on an ice bath under argon atmosphere. To the solution was added vinylmagnesium bromide in tetrahydrofuran (0.3 ml, 0.3 mmol, 1.0M), and the mixture was warmed to room temperature and stirred for 10 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(2-tetrahydropyranyl)oxy-1,6,10-dodecatrien-3-ol (61 mg, 70%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
The subtitle compound was prepared by the method of example 1 step (iv) using ethyl bromoacetate and 4-chloro-2-nitrophenol Yield 1.4 g
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=O>>[CH3:34][CH:35]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)CCCC(C)CC=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)CCCC(C)CC=CCc1ccccc1
Yield: 55.1 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.85 g, 8.61 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 5.4 mL, 8.61 mmol, 1.0 equiv.) and 3,7-dimethyloctanal (2.02 g, 12.9 mmol, 1.5 equiv.), 1.16 g (55%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1I.[CH3:23][N:24](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[C:23]#[N:24]
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(I)c(Br)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(C#N)c(Br)c12
Temperature: 95 °C
Yield: 83 %

Procedure:
A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H -carbazole-1-carboxamide (0.609 g, 1.29 mmol) and zinc cyanide (0.076 g, 0.644 mmol) in DMF (7 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.074 g, 0.064 mmol) and heated overnight at 95° C. The cooled mixture was diluted with EtOAc, washed twice with 10% aqueous LiCl, then with brine. The aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was triturated and sonicated with DCM and the precipitate was collected by filtration to give 4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a pale yellow solid (0.400 g, 83% yield). Mass spectrum m/z 372, 374 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.55 (d, J=8.6 Hz, 1H), 8.38 (s, 1H), 8.31 (br. s., 1H), 8.03 (s, 1H), 7.74 (br. s., 1H), 7.49 (dd, J=8.6, 1.1 Hz, 1H), and 1.52 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([O:6][CH2:7][C:8]2[N:9]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:21][CH2:20]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:44][CH:45]=1
Reactant: Clc1ccc(OCc2cc3ccccc3n2CCC2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: O=CO
Product: Clc1ccc(OCc2cc3ccccc3n2CCC2CCNCC2)cc1
Temperature: 0 °C

Procedure:
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-[2-(1-tritylpiperidin-4-yl)ethyl]-1H-indole was dissolved in 7.0 ml of methylene chloride. The reaction solution was then placed on an ice bath and formic acid (0.3383 g) was added. The resulting mixture was stirred in the ice bath for about five hours. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14]C)=[O:13])=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=[CH2:18].[OH-].[Na+].Cl>O1CCOCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=[CH2:18]
Reactant: C=CCn1c(=O)ccc2ncc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1c(=O)ccc2ncc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of methyl 6-oxo-5-(2-propen-1-yl)-5,6-dihydro-1,5-naphthyridine-3-carboxylate (0.809 g, 3.32 mmol) in 1,4-dioxane (10 ml) and water (5 ml) was added 2M NaOH (2 ml) and the reaction was stirred at rt for 2 h. The pH of the mixture was then adjusted to 2-3 with 2M HCl and extracted three times with EtOAc. The combined organic phases were then dried and evaporated to give the desired product as a solid (0.689 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 2.5 °C
Yield: 99.5 %

Procedure:
A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5° C., thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22° C. overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45° C., the residue treated with toluene and re-concentrated (3×2.250 L, 3×2 vol) under reduced pressure at 40 to 45° C. to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([C:9]([O:11][CH2:12]C)=[O:10])=[CH:7][O:8][C:4]=2[CH:3]=1>CO>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1coc2cc(N)ccc12
Solvent: CO
Product: COC(=O)C1COc2cc(N)ccc21
Reaction time: 8 h

Procedure:
A mixture of ethyl 6-amino-1-benzofuran-3-carboxylate (2.0 g, 9.8 mmol) in 50 mL of MeOH was added Mg filings (1.17 g, 49 mmol) ans the mixtrue was stired overnight at room temperature. The mixture was filtered and the filtrate was concentrated. The residue was then partitioned between EtOAc and water. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silca gel column chromatograph to give methyl 6-amino-2,3-dihydro-1-benzofuran-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CCCCC2)c(Cl)cc1CCO
Reaction time: 2 h

Procedure:
A solution of 14.2 g (50 mmole) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid in 50 ml of absolute tetrahydrofuran is added dropwise over a period of approximately 15 minutes to a suspension of 1.6 g (42 mmole) of lithium aluminium hydride in 90 ml of absolute tetrahydrofuran. The whole is subsequently stirred for a further 2 hours at 50°. After the addition of 50 ml of water, the whole is filtered over Hyflo and then washed with THF. The solvent is concentrated in a vacuum rotary evaporator and the residue is partitioned between ether and water. The ether phases are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using chloroform/ethyl acetate (1:1) as eluant. Recrystallisation from ether/petroleum ether yields 2-[5-chloro-2-methoxy-4-(piperidin-1-yl)-phenyl]-ethanol having a melting point of 56°-57°.
Reaction SMILES: [C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[C:11]([F:24])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[C:11]([F:24])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1F
Yield: 92.5 %

Procedure:
The general hydrolysis procedure, described for 195 was followed. Thus, 1,1-dimethylethyl (2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoate (198) (0.380 g, 0.9 mmol) in CH2Cl2 was treated with TFA to afford 0.305 g (92%) of the title compound as an off-white foam. 1H NMR (300 MHz, CD3OD): δ 7.76 (d, J=15.9 Hz, 1H), 7.59 (app t, J=7.8 Hz, 1H), 7.18 (app t, J=7.8 Hz, 1H), 7.04 (br d, J=8.1 Hz, 1H), 6.94 (br d, J=11.7 Hz, 1H), 6.67-6.60 (m, 3H), 6.56 (d, J=16.2 Hz, 1H), 2.34 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 365 (M−H)−. Anal. Calcd for C23H23FO3.1.5H2O, C, 70.38, H, 6.63, F, 4.84; Found: C, 69.96, H, 5.95, F, 4.73.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](I)[CH3:26]>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (55% suspension in oil, 1.65 g) was added to a solution ethyl 3-(4-benzyloxyphenyl)lactate (10.30 g), which is the product of Reference example 1(b), in a mixture of N,N-dimethylacetamide (50 ml) and toluene (50 ml). The mixture was stirred at 40° C. for 30 minutes. To the reaction mixture were added ethyl iodide (3.3 ml) and toluene (5 ml). This mixture was stirred at 40° C. for 2 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=5/1 as the eluant to give the desired compound (5.50 g) as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10]([C:12]([CH2:17][CH3:18])(CO)CO)[CH3:11].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:10]([C:12]1([CH2:17][CH3:18])[CH2:1][O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH3:11]
Reactant: COc1cscc1OC
Reactant: CCC(CC)(CO)CO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCC1(CC)COc2cscc2OC1
Temperature: 25 °C
Yield: 68 %

Procedure:
3,4-Dimethoxythiophene (5.0 g, 34.7 mmol), 2,2-diethyl-1,3-propanediol (36.4 mmol), toluenesulfonic acid (0.2 g), and dry toluene (200 mL) were placed in a 500 mL round bottom flask equipped with a soxhlet extractor that contained a molecular sieve (4A)-filled extraction thimble. The solution was refluxed for 12 h under argon atmosphere, then cooled to 25° C. The solvent was removed under reduced pressure, the mixture diluted with 250 mL diethyl ether, extracted with 5% ammonium hydroxide (200 mL), and the extracted with water (2×200 mL). The organic layer was dried over anhydrous magnesium sulphate and the ether distilled off under reduced pressure, leaving an oil. This oil was further purified using column chromatography (silica and hexanes/ethyl acetate, 90/10) to yield 3,3-diethyl-3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepine as a colourless oil in 68% yield.