Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[C:10](=O)[CH2:9][CH2:8]3)=[CH:3][CH:2]=1.[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:32]CCCl>>[ClH:32].[CH3:15][N:16]([CH3:17])[CH:10]1[CH2:9][CH2:8][C:7]2([C:4]3[CH:5]=[CH:6][C:1]([CH3:14])=[CH:2][CH:3]=3)[CH:11]1[CH2:12]2
Reactant: Cc1ccc(C23CCC(=O)C2C3)cc1
Reactant: ClCCCl
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ccc(C23CCC(N(C)C)C2C3)cc1
Product: Cl
Reaction time: 5 h

Procedure:
The mixture of 5-p-tolyl-bicyclo[3.1.0]hexan-2-one (100 mg, 0.535 mmol) in DCE (3 mL) and dimethylamine (2M solution in THF, 6 mL, 5.3 mmol) was treated with sodium triacetoxyborohydride (113 mg, 0.53 mmol) at room temperature. The reaction mixture was stirred for 5 h, then the reaction mixture was concentrated, diluted with saturated NaHCO3, extracted with CH2Cl2 (3×), dried over K2CO3, filtered and concentrated in vacuo. The oily crude residue was converted to HCl salt (124 mg, 91.7%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (t, 1 H) 1.73-1.80 (m, 1 H) 1.90-1.95 (m, 1 H) 2.01-2.21 (m, 3 H) 2.33-2.38 (m, 1 H) 2.81 (d, 2 H) 2.91 (d, 3 H) 3.70-3.84 (m, 1 H) 7.01-7.13 (m, 4 H). 13C NMR (400 MHz, CHLOROFORM-d) d ppm 15.70 (s, 1 C) 21.20 (s, 1 C) 24.79 (s, 1 C) 25.82 (s, 1 C) 31.66 (s, 1 C) 33.81 (s, 1 C) 43.55 (s, 1 C) 43.69 (s, 1 C) 70.51 (s, 1 C) 126.70 (s, 2C) 129.38 (s, 2C) 136.31 (s, 1C) 139.58 (s, 1 C). MS (M+1) 216.
Reaction SMILES: [CH3:1]C(C)([O-])C.[Na+].IC.[O:9]=[C:10]1[NH:15][C:14]2[CH:16]=[C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:18][C:13]=2[CH:12]=[CH:11]1.O>C1COCC1>[CH3:1][N:15]1[C:10](=[O:9])[CH:11]=[CH:12][C:13]2[NH:18][C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:14]1=2
Reactant: O=c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cn1c(=O)ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc21
Reaction time: 20 h

Procedure:
Sodium tert-butoxide (10 mg, 0.11 mmol, 1.0 equiv) and iodomethane (13 μL, 0.22 mmol, 2.0 equiv) were added sequentially to a suspension of the product from Example 3 (30 mg, 0.11 mmol, 1 equiv) in THF (10 mL) at 23° C. The reaction mixture was stirred for 20 hours. Additional sodium tert-butoxide (20 mg, 0.22 mmol, 2.0 equiv) and iodomethane (26 μL, 0.44 mmol, 4.0 equiv) were added in 2 equal portions over 1 hour, and then the reaction mixture was allowed to stir an additional 1 hour. Water (5 mL) was added, and the resulting mixture was concentrated to a volume of 2 mL. The mixture was purified by reverse phase HPLC to afford the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:28]([F:31])([F:30])[F:29])=[CH:10]\[C:11]([C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]3([CH3:24])[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:27])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C1C=C(NC(N[C@H]([C@@H]2C[C@@H]3CCN2C[C@@H]3CC)C2C3C(=CC=C(OC)C=3)N=CC=2)=S)C=C(C(F)(F)F)C=1.[Cl-].[NH4+].[N+:75]([CH3:78])([O-:77])=[O:76]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]([CH2:78][N+:75]([O-:77])=[O:76])([C:28]([F:31])([F:30])[F:29])[CH2:10][C:11]([C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]3([CH3:24])[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:27])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Reactant: C[N+](=O)[O-]
Agent: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccnc2ccc(OC)cc12
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1(C)CSC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.100 g, 0.205 mmol) and 1-[3,5-bis(trifluoromethyl)phenyl)-3-{(S)[(2S,4S,5R)-5-ethyl-1-aza-bicyclo[2.2.2]oct-2-yl]-(6-methoxy-4-quinolinyl)methyl}thiourea (0.0305 g, 0.020 mmol) were dissolved in nitromethane (2.0 ml) and the resulting solution was stirred at 60° C. for 3 days. The reaction mixture was cooled to room temperature and aqueous saturated ammonium chloride was added. The resulting mixture was extracted with dichloromethane (3×) and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.021 g, 19%) as a light yellow solid. Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=70:30, 1 ml/min, retention time 5.71 minutes (major enantiomer), 8.13 minutes (minor enantiomer)) indicated that the reaction proceeded with 79% enantioselectivity. 1H NMR (400 MHz, CDCl3) δ 7.82-7.78 (m, 2H), 7.47 (d, 1H), 7.43-7.41 (m, 1H), 7.19 (s, 2H), 5.90 (s, 1H), 5.60 (d, 1H), 5.45 (d, 1H), 4.13 (d, 1H), 3.97 (d, 1H), 3.88 (d, 2H), 3.09 (d, 2H), 2.53 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:14]3[N:15]([CH3:35])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26]C(OC(C)(C)C)=O)[CH:22]=[CH:21][C:20]=4[Cl:34])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:14]3[N:15]([CH3:35])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[CH:21][C:20]=4[Cl:34])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (1.35 g; 2.03 mmol) and TFA (3.47 g; 30.5 mmol) in DCM (75 mL) was stirred over night at rt. The mixture was cooled to 0° C. and basicified to pH ˜10 and extracted with DCM. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was washed with a mixture of Et2O and petroleum ether to give the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH:37]3[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]3)[CH:36]=2)O1>>[C:44]([O:43][C:41]([N:39]1[CH2:40][CH:37]([N:35]2[CH:36]=[C:32]([C:2]3[CH:23]=[CH:22][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)[CH:33]=[N:34]2)[CH2:38]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)ccc1-2

Procedure:
Similarly to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate to give 3-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48](C)[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].COC(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH2:48][CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1)C(C)C
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Product: CC[C@H](NC(=O)OC)C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1

Procedure:
This compound was made in an analogous manner to methyl (S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)butanoic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling. LCMS-ESI+: calculated for C47H48N8O7: 836.93; observed [M+1]+: 837.63.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]#[C:8][CH2:9][CH2:10][OH:11])[CH:4]=[N:3][CH:2]=1>C(O)(C)C.[Pd]>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:4]=[N:3][CH:2]=1
Reactant: OCCC#Cc1cncnc1
Agent: [Pd]
Solvent: CC(C)O
Product: OCCCCc1cncnc1
Yield: 80 %

Procedure:
A solution of 18.5 g of 4-(5-pyrimidinyl)-3-butyn-1-ol in 300 ml of isopropanol was hydrogenated over a total of 3.5 g of 10% palladium on carbon added in three portions. Evaporation of the solvent and distillation of the residue gave 15.2 g (80%) of 5-pyrimidinebutanol, bp 175°-180° C./0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22].[ClH:23]>CO>[ClH:1].[ClH:23].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CO
Product: COc1cc(N2CCNCC2)ccc1Cl
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A 4-L beaker equipped with a mechanical stirrer was charged with tert-butyl 4-(4-chloro-3-methoxyphenyl)piperazine-1-carboxylate (500 g, 1.53 Mol, 1 equiv) and MeOH (1.50 L). While stirring at room temperature conc. 37% HCl (500 mL, 4 equiv) was added over 5 min. The internal temperature rose to 40° C., and the solution became thick with precipitate. After 15 min, the mixture was heated to an internal temperature of 60° C. on a hotplate. (Foaming begun at approximately 50° C. as the mixture warms.) After 2 h at 60° C., the solution was cooled to room temperature, and subsequently to 5° C. in a refrigerator. The product was collected by filtration in two batches. Each batch of the red-brown filtrate was washed with EtOAc (2×500 mL) to give a light yellow solid. The two batches were combined to afford the product (391.3 g). The filtrate was concentrated to a volume of 300 mL in vacuo and treated with hot (50° C.) MeOH (500 mL). The mixture was cooled to 5° C. in a refrigerator for 24 h. The resulting precipitate was collected by filtration and washed with EtOAc (2×200 mL) to afford an additional 44.3 g of product (total of 435.6 g, 95% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH3:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])[CH3:4].[CH3:20]I.[Na+].[Cl-]>C1COCC1.O.C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:20])[CH:10]=[C:11]([CH3:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c(C)cn1C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Sodium hydride (436 mg, 60% in mineral oil, 10.9 mmol) was added to a solution of 4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.25 g, 5.45 mmol) in THF (10 mL) at 0° C. and under nitrogen as inert gas and the reaction mixture was stirred for 15 min. Then methyl iodide (1,547 g, 10.9 mmol) was added to the reaction mixture and the reaction mixture was stirred for 1 h at 0° C. and overnight at RT. After the addition of a few drops of water and aq. sat. NaCl solution (250 mL), extraction was performed with DCM (2×250 mL). After drying of the combined organic phases over sodium sulfate, filtration and removal of the solvent, purification was performed by means of column chromatography. The desired product 1,4-dimethyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.02 g, 77% of theoretical) was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1([CH3:11])[CH2:10][O:9][CH2:8]1>O>[N:1]([CH2:6][C:7]1([CH3:11])[CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CC1(CBr)COC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CC1(CN=[N+]=[N-])COC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A 5 liter jacketed flask equipped with a mechanical stirrer was charged with 1062 grams of sodium azide, 1972 ml of water, and 2450 grams of 3-bromomethyl-3-methyloxetane (supplied by AmeriBrom, Inc. of New York). This mixture was brought to reflux with vigorous mixing. After 48 hours the mixture was cooled to room temperature. The organic layer was separated off and washed three times with 1000 ml of water before being dried over molecular sieves to yield pure 3-azidomethyl-3-methyloxetane at 85% yield.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Br)[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.FC1C=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19]2.C[C@H]1N[C@@H](C)C[NH:28][CH2:27]1>>[F:14][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[N:21]1[CH2:20][C@H:19]([CH3:18])[N:28]([CH3:27])[C@H:23]([CH3:24])[CH2:22]1)[NH:4][CH2:5][CH2:6]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CC(=O)N1CCc2cc(F)c(Br)cc21
Product: C[C@@H]1CN(c2cc3c(cc2F)CCN3)C[C@H](C)N1C

Procedure:
The title compound was prepared from 1-acetyl-6-bromo-5-fluoroindoline (prepared by bromination of 5-fluoroindoline analogous to procedure in J. Het. Chem. 1983, 20, 349, followed by N-acylation) by reaction with cis-3,5-dimethylpiperazine using similar procedure to Description 2 (82%), followed by N-methylation using procedure similar to Description 24 (69%), followed by hydrolysis as in Description 3 (96%). The product was isolated as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:6]([N:8]1[CH2:13][CH2:12][CH:11](C2OC3C=CC=CC=3C=2)[CH2:10][CH2:9]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[O:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:38]1[O:37][C:41]2[CH:24]=[CH:25][CH:3]=[CH:4][C:40]=2[CH:39]=1
Reactant: COc1cc(C(=O)N2CCC(c3cc4ccccc4o3)CC2)cc(OC)c1OC
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: COc1cc(CN2CCCCC2c2cc3ccccc3o2)cc(OC)c1OC

Procedure:
A solution of 27.6 g of 1-(3,4,5-trimethoxybenzoyl)-4-(2-benzofuranyl)-piperidine in 150 ml of tetrahydrofuran is added dropwise to a refluxing solution of 4.0 g of lithium aluminium hydride in 120 ml of tetrahydrofuran. After 4 hours' refluxing, the reaction mixture is cooled, and the excess lithium aluminium hydride decomposed at -10° by means of 4 ml of water. The reaction solution is filtered off under suction, the filter residue then washed with 1 liter of chloroform, and the combined filtrates concentrated in vacuo. The residue is dissolved in 500 ml of 10% aqueous methanesulphonic acid, and the acid solution washed with ether. The aqueous phase is thereupon adjusted to pH 12 by addition of 30% sodium hydroxide solution, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered, and concentrated by evaporation to obtain crude 1-(3,4,5-trimethoxybenzyl)-2-(2-benzofuranyl)-piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from ethyl acetate, whereupon it melts at 212°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([S:19]([C:22]1[CH:27]=[CH:26][C:25](F)=[C:24]([Cl:29])[CH:23]=1)(=[O:21])=[O:20])[CH3:18]>>[Cl:29][C:24]1[CH:23]=[C:22]([S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[CH:27]=[CH:26][C:25]=1[O:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CC(C(=O)O)c1cc(O)cc(C(F)(F)F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(C(C)C(=O)O)cc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 50 step (iii) and the product from example 3 step (i).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:34](=[O:35])[CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2c(C)cccc2C)CC1

Procedure:
To a stirred solution of 8 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 4 parts of pyridine and 80 parts of benzene are added dropwise 7.7 parts of benzeneacetyl chloride in 40 parts of benzene. After the addition is complete, the whole is heated to reflux and stirred at reflux temperature for 3 h. 45. The reaction mixture is cooled and filtered. The benzene-phase is washed with water and then with sodium hydrogen carbonate solution and with water. After evaporation, an oily residue is obtained, which solidifies on triturating in 1,1'-oxybisethane, to yield 5 parts of ethyl 4-[N-(2,6-dimethylphenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate; mp. 106° C.
Reaction SMILES: Br.[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH:7]([O:9][C:10]1[C:11]([CH3:18])=[C:12]([NH2:17])[CH:13]=[CH:14][C:15]=1[CH3:16])[CH3:8].[C:19](Cl)(Cl)=[O:20].[CH2:23]([OH:25])[CH3:24]>C(#N)C.C1(C)C=CC=CC=1>[OH2:9].[NH:4]1[CH2:5][CH2:6][N:2]=[C:3]1[CH:7]([O:9][C:10]1[C:11]([CH3:18])=[C:12]([NH:17][C:19](=[O:20])[O:25][CH2:23][CH3:24])[CH:13]=[CH:14][C:15]=1[CH3:16])[CH3:8].[CH2:23]([O:25][C:19](=[O:20])[NH:17][C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:10]([O:9][CH:7]([C:3]2[NH:4][CH2:5][CH2:6][N:2]=2)[CH3:8])[C:11]=1[CH3:18])[CH3:24]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(N)c(C)c1OC(C)C1=NCCN1
Reactant: CCO
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)Nc1ccc(C)c(OC(C)C2=NCCN2)c1C
Product: O
Reaction time: 1 h

Procedure:
To a stirred suspension of the title product of Example 7 (5.0 g, 15.9 mmole) in 130 ml of acetonitrile was added 13.8 ml (ca. 16 mmole) of 12% phosgene in toluene. After 18 hours 25 ml absolute ethanol was added, and the mixture was stirred for one hour. Volatiles were removed in vacuo and the residue was dissolved in water. After adjusting to pH 10 with dilute sodium hydroxide, the solution was extracted with two portions of diethyl ether, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The solid that crystallized during the concentration was triturated with diethyl ether and collected by filtration to give 2.2 g of the title compound as the hemihydrate. Structure assignment was supported by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:27]=2[CH3:40])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2>CO.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:27]=2[CH3:40])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccc(OCCCS(C)(=O)=O)c5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OCCCS(C)(=O)=O)cccc1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Yield: 48.1 %

Procedure:
Methyl 2-((3S)-6-((1R)-7-fluoro-4-(2-methyl-3-(3-(methylsulfonyl)propoxy)phenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-32; 64 mg) in methanol (3 mL) and aqueous NaOH (1 M; 0.5 mL) is stirred for 16 hours, concentrated under vacuum, acidified with aqueous HCl (1 M) and extracted with diethyl ether. A precipitate that forms is collected by filtration, washed with some n-hexane, dried and subsequently triturated with a mixture of n-hexane and diethyl ether to give the title compound (30 mg). LC (method 20): tR=6.15 min; Mass spectrum: m/z=555 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[C:20]([OH:22])[C:19]3C[C:18]=3[C:17]=2O)[C:11]([O:13]CC)=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2].[CH3:30][OH:31]>>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:17]=[CH:18][C:19]3[O:31][CH2:30][O:22][C:20]=3[CH:21]=2)[C:11]([OH:13])=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1cc(O)c2c(c1O)C2
Reactant: CO
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A 1 L 3 necked 24/40 round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with a solution of 76.3 g 0.185 mol) of the semi-purified product of Step A dissolved in 500 mL of methanol. The flask was purged with nitrogen, the stirrer was started, and 37 mL of a 5.0N aqueous solution of sodium hydroxide was added over a 30 minute period via an addition funnel. The reaction mixture was stirred at room temperature for an additional 30 minutes at which point TLC analysis (CH2Cl2 -MeOH-NH4OH 90:10:1) indicated that the starting material had been consumed. The reaction mixture was adjusted to pH=4 with 6N HCl, and the bulk of the organic solvent was removed in vacuo. The precipitated organic product and the aqueous layer were next partitioned between CH2Cl2 (1 L) and water (1 L) which produced a copious emulsion. The reaction mixture was then aged overnight in a refrigerator which resulted in crystallization of the organic product. The crystalline solid was separated from the two phase mixture by filtration and washed with CH2Cl2. The solid was slurried again in diethylether, filtered, washed with hexane, and then dried in a vacuum to afford 65 g (94%) of the title compound as a white crystalline solid.