Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14].[BH4-].[Na+].CO.ClCCl.CO>C(O)(C)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([CH3:14])[OH:15]
Reactant: CC(=O)c1c(C)nc2ccccc2c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2ccccc2c(N)c1C(C)O
Temperature: 25 °C
Yield: 74.3 %

Procedure:
1-(4-amino-2-methyl-3-quinolinyl)-ethanone (2 g) was added all at once as a solid to a stirred suspension of sodium borohydride (1.13 g) in isopropanol (50 ml). The mixture was refluxed for several hours until the reaction was complete based on thin-layer chromatography (silica gel, 10% methanol/dichloromethane). Methanol (10 ml) and water (5 ml) were added and the mixture was allowed to cool slowly to room temperature. Most of the solvent was evaporated under vacuum, and the concentrate partitioned between water and ethyl acetate. The ethyl acetate extract was dried (saturated sodium chloride wash, sodium sulfate) and the ethyl acetate removed under vacuum. The resulting solid was recrystallized from acetonitrile to give 1.5 g of crystals, mp 214°.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12]C)=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1.Br.CC(O)=O>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: COc1c(C(=O)O)cc(F)c2ccccc12
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc(F)c2ccccc2c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To 10.1 g 4-fluoro-1-methoxynaphthalene-2-carboxylic acid 55 mL HBr/HOAc were added and the mixture was stirred and heated. After 30 min at 60° C. another 7.5 mL of HBr/HOAc were added, and after an additional 30 min at 80° C. the mixture was cooled to ambient temperature and left standing overnight. The reaction was then poured into ice/water and the precipitated solid was filtered and washed with water, followed by 1% ether in heptane and then by heptane. The solid was dried in vacuo at 40° C. to yield 7.7 g 4-fluoro-1-hydroxynaphthalene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:13][C:9]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cccnc1-n1cccc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccnc1-n1cccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.4 %

Procedure:
To a solution of 3.0 g of 3-chloro-2-(1H-pyrrol-1-yl)pyridine in 30 ml of N,N-dimethylformamide was added 3.1 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 2-(2-bromo-1H-pyrrol-1-yl)-3-chloropyridine of the formula:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([C:17]3([CH3:21])[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:22])=[CH:7][C:3]=1[C:4](O)=[O:5].CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:41][C:42]1([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:45][NH:44][CH2:43]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([C:17]3([CH3:21])[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:22])=[CH:7][C:3]=1[C:4]([N:44]1[CH2:43][C:42]([C:46]2[CH:47]=[CH:48][C:49]([C:50]#[N:51])=[CH:52][CH:53]=2)([F:41])[CH2:45]1)=[O:5]
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1cc(C)c(-c2[nH]c(C3(C)COC3)nc2C)cc1C(=O)O
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(C3(C)COC3)nc2C)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 2,4-dimethyl-5-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 175.4) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 459 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 11.73 (br, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.25 and 7.24 (2 singlets, Ar—H, 1H), 7.19 and 7.16 (2 singlets, Ar—H, 1H), 4.94-4.86 (m, 2H), 4.57-4.35 (m, 6H), 2.36 and 2.34 (2 singlets, CH3, 3H), 2.29 and 2.19 (2 singlets, CH3, 3H), 2.14 and 2.00 (2 singlets, CH1, 3H), 1.67 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[NH:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]3([C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36][NH:35][CH2:34]3)[CH2:30][CH2:29]1)=[O:27])[CH2:22]2.Cl>C(Cl)Cl>[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[NH:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]3([C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36][N:35]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34]3)[CH2:30][CH2:29]1)=[O:27])[CH2:22]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A vial, equipped with a flea stir bar, was charged with methanesulfonyl chloride (4.5 μL, 58 μmol), DIEA (15 μL, 90 μmol) and CH2Cl2 (1 mL). A solution of N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (25 mg, 53 μmol) in CH2Cl2 (1 mL) was added and the mixture was stirred overnight. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford N-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (8 mg, 33%). LC-MS Method 1 tR=1.89 min, =458; 1H NMR (CDCl3) δ=1.60-2.15 (18H), 2.92 (s, 3H), 3.13 (m, 2H), 3.51 (s, 2H), 3.90 (d, 2H), 3.99 (s, 1H), 4.45 (s, 2H), 4.88 (1H), 7.05-7.40 (4H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:42]=[CH:41][C:18]([CH2:19][NH:20][C:21]([C:23]2([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21]([C:23]2([CH2:36][CH2:37][CH2:38][CH2:39][N:11]3[CH2:12][CH2:13][N:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH2:9][CH2:10]3)[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:41][CH:42]=1
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cc1cccc(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluorobenzyl-amide.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[CH3:36])C.[OH-].[Na+].Cl>C(O)C>[CH2:34]([CH:31]([CH2:32][CH3:33])[CH2:30][O:29][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])=[C:8]([CH3:36])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:17]=1)[CH3:35]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(CC)CC)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)COc1cc(C#CCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(C)c2)c1
Reaction time: 16 h

Procedure:
{4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (210 mg; 0.40 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 144 mg (73%). HPLC-MS: m/z: 498.2 (M+H)+; Rt: 1.97 min.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[Br:6][C:7]1[C:8]([Cl:15])=[N:9][CH:10]=[C:11]([CH2:13]Br)[CH:12]=1>CN(C)C=O.O>[Br:6][C:7]1[C:8]([Cl:15])=[N:9][CH:10]=[C:11]([CH2:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=1
Reactant: Clc1ncc(CBr)cc1Br
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1cnc(Cl)c(Br)c1
Temperature: 65 °C
Yield: 84.4 %

Procedure:
Sodium methanesulfinate (0.748 g, 7.32 mmol) and the product from Example 143A (1.9 g, 6.66 mmol) were combined in N,N-dimethylformamide (4.44 mL) and heated at 65° C. for 1 hour. The reaction mixture was cooled and diluted with 200 mL of cold water producing a precipitate that was collected by filtration and dried to constant mass affording the title compound (1.6 g, 84%).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>C(O)C.O>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Reaction time: 3 h
Yield: 101 %

Procedure:
A solution of sodium hydroxide (0.63 g) in ethanol (14 ml) was added dropwise to a solution of ibandronic acid (5 g) in water (50 ml) at room temperature. The obtained slurry was stirred for 3 hours to obtain a pH of 4.1. The precipitate was isolated by vacuum filtration, washed with ethanol (2×25 ml) and dried in a vacuum oven at 50° C. for 22 hours to obtain 5.4 g of ibandronate sodium crystal form QQ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.[N:38]1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[CH2:44][NH2:45]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:45][CH2:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][N:38]=1)=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1cnccn1
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2cnccn2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-pyrazin-2-yl-methylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].C(O)(=O)C.N1CCCCC1>C(O)(C)C.C(Cl)Cl>[C:13]([C:12](=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[Cl:1])[C:11]([O:17][CH3:18])=[O:16])(=[O:14])[CH3:15]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccc(F)cc1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g (315 mmol) of 2-chloro-4-fluoro-benzaldehyde and 36.6 g (315 mmol) of methyl acetoacetate are dissolved in 150 ml of isopropanol and admixed with 1.7 ml of piperadine acetate. The mixture is stirred at room temperature overnight and then diluted with methylene chloride and extracted with water, dried over sodium sulphate and concentrated. The crude product is reacted further, as cis-trans mixture.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=1)[C:3]#[N:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:43]=[CH:44][CH:45]=1)[CH2:22][C@@H:23]([C:40](O)=[O:41])[NH:24][C:25](=[O:39])[CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:17][O:16][C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:6][CH2:5][CH:2]([NH:1][C:40](=[O:41])[C@H:23]([CH2:22][C:21]1[CH:43]=[CH:44][CH:45]=[C:19]([CH3:18])[CH:20]=1)[NH:24][C:25](=[O:39])[CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:3]#[N:4])=[O:15]
Reactant: COC(=O)c1cccc(OCCC(N)C#N)c1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc(OCCC(C#N)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1
Reaction time: 1.5 h

Procedure:
To a solution of 2-amino-4-[3-(methoxycarbonyl)-phenoxy]-butyronitrile (0.5 g, 2.13 mmol), 3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanine (see example 1, 0.80 g, 2.13 mmol) and diisopropylethylamine (1.1 mL, 6.39 mmol) in CH2Cl2 (15 mL) is added benzotriazol-1-yloxy-tris-(pyrrolidino)-phosphonium hexafluorophosphate (PyBop, 1.22 g, 2.34 mmol) in one portion. After stirring 1.5 hour, an additional portion of PyBop (0.61 g, 1.2 mmol) is added, and the solution is stirred overnight. The reaction mixture is washed with 1 N HCl (50 mL), saturated aqueous NaHCO3 (1×50 mL), water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and evaporated. The residue is chromatographed (silica, 50% EtOAc/hexane) to yield N-[3-(3-(methoxycarbonyl)-phenoxy)-1-cyanopropyl]-3-methyl-Nα-(2,2-diphenylacetyl)-L-phenylalaninamide as a white solid, m.p. 152-153° C.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11](=[O:47])[C:12]([C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1)=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:15]=1>CS(C)=O.O.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:12]1([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:44])=[O:45])=[CH:41][CH:42]=2)[CH2:2][CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:15]=1)=[O:47]
Reactant: COC(=O)C(=Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C1(c2ccc(S(C)(=O)=O)cc2)CC1c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a suspension of trimethylsulfoxonium iodide (400 mg, 1.83 mmol) in DMSO (25 mL) at 0° C. was added NaH (60%, 73 mg, 1.83 mmol). After 30 min., 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester from Step 2 (688 mg, 1.22 mmol) was added and the resulting reaction mixture stirred for 18 h at 21° C., then diluted with water and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with toluene/acetone, 80:20) provided the 2-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-1-(4-methanesulfonyl-phenyl)-cyclopropanecarboxylic acid methyl ester compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.C[Si]([N:28]=[N+:29]=[N-:30])(C)C>ClCCl>[CH2:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:3]2[N:2]([CH3:1])[N:30]=[N:29][N:28]=2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CNC(=O)C1CCN(Cc2ccccc2)CC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1nnnc1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1-benzyl-piperidine-4-carboxylic acid methylamide (36) (853 mg, 3.67 mmol) in dichloromethane (10 ml) was cooled in an ice-bath and phosphorous pentachloride (841 mg, 4 mmol) was added dropwise. The mixture was stirred at rt for 5 h, cooled to −5° C. and trimethylsilyl azide (387 ul, 3.67 mmol) was added dropwise. The reaction mixture was stirred for 3 h at rt and was then quenched by addition of sat. aqueous NaHCO3 solution. The organic layer was washed with water and brine, dried over Na2 SO4 and evaporated to yield a colorless solid.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](OC)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].CO>CCCCCCC.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Solvent: CCCCCCC
Product: COC(=O)CCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1

Procedure:
A solution of 6.0 g (35 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine and 11.4 g (78 mmol) dimethyl succinate in 60 mL of heptane is brought to reflux. 0.05 mL of tetraisopropyl orthotitanate is added and the reaction mixture is refluxed for 16 hours while the evolved methanol is trapped in a Dean-Stark trap. The reaction mixture is then concentrated and the title compound is isolated as a red oil after column chromatography and melts at 76° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[CH:7]([Si:9]([CH3:12])([CH3:11])Cl)=[CH2:8].C(N(CC)CC)C>O1CCCC1>[CH:4]([N:3]1[CH:7]([SiH:9]([CH3:12])[CH3:11])[CH2:8][O:6][C:2]1=[O:1])=[CH2:5]
Reactant: O=C1NCCO1
Reactant: C=C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CN1C(=O)OCC1[SiH](C)C

Procedure:
A 3-vinyldimethylsilyl-2-oxazolidinone was prepared in accordance with the following procedure. A mixture of 34.8 grams of 2-oxazolidinone and 48.17 grams of vinyldimethylchlorosilane was prepared in 750 ml of tetrahydrofuran solvent. 40.26 grams of triethylamine was added dropwise. The mixture was then heated in a distillation apparatus with continuous reflux for a period of 30 minutes.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:2][CH:3]2[O:7][CH2:6][CH2:5][O:4]2)[CH:13]=1)[CH3:9]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCC2OCCO2)c1
Temperature: 25 °C

Procedure:
2-Bromomethyl-1,3-dioxolane (8.3 ml, 80 mmol), ethyl-3-hydroxy-benzoate (3.32 g, 20 mmol), potassium carbonate (5.53 g, 40 mmol) and sodium iodide (1.2 g, 8 mmol) were heated at 120° C. in DMF (8 ml) for 17 hrs. The reaction was cooled to room temperature and all the solvents were evaporated under reduced pressure. The residues were partitioned between DCM (250 ml) and water (250 ml). The DCM layer was separated and the aqueous layer was back-extracted with DCM (2×100 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography (4×25 cm). The product was eluted with 20% petroleum ether (60-80° C.) in DCM and the title compound was obtained as a slightly brown oil (4.63 g, 91.8%). APCI-MS, m/z 252.95 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24]C3CCCCO3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(OCCCCOC3CCCCO3)nc2-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: CO
Product: OCCCCOc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
2.39 g of 1-(5,6-diphenylpyrazin-2-yloxy)-4-(2-tetrahydropyranyloxy)butane was dissolved in methanol and 1.53 g of pyridium p-toluenesulfonate was added, and then the mixture was refluxed for 30 minutes. The reaction solution was cooled, poured into ice water while stirring and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 1.74 g of the desired compound as a colorless crystal having a melting point of 93 to 95° C.
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(C)C)(C)C>CO>[C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCC(=O)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CO
Product: OCC[C@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 2396.7 %

Procedure:
In a 200 ml stainless steel-made autoclave were charged 426.5 mg of [RuI(p-cymene)(R)-Tol-BINAP]I3 prepared in Example 2, the diisopropyl ether solution of 3-phenyl-3-oxopropanal prepared in Reference Example 2, 100 ml of methanol, and 2.0 ml of degassed purified water in a nitrogen atmosphere, followed by stirring the mixture at 50° C. for 22 hours under a hydrogen pressure of 50 atm. The reaction mixture was concentrated and subjected to silica gel column chromatography (eluent: hexane/isopropanol=9/l by volume) to eliminate the complex. The obtained hydrogenation product was dissolved in a 6-fold amount of diisopropyl ether by heating and allowed to stand at 0° C. for 24 hours. The resulting precipitate was collected by filtration and dried (room temperature, 1 mmHg), and 10.5 g of (1S)-phenyl-1,3-propanediol was obtained as a colorless crystal (percent yield: 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][NH2:11]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:11][CH3:10])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CN
Reactant: Clc1cc(Cl)nc(Cl)c1
Solvent: CCO
Product: CNc1cc(Cl)nc(Cl)c1
Temperature: 22.5 °C
Reaction time: 14 h

Procedure:
2,4,6-Trichloropyridine (1800 g, 9.89 mol) was dissolved in ethanol (1800 mL). Methylamine 40% solution in ethanol (6.3 L) was added over 1 h and 40 min maintaining the reaction temperature between 20-25° C. The reaction was stirred for 14 hours at room temperature and concentrated. The product was filtered, washed with methyl t-butyl ether (1,500 ml) and dried to yield A1.6 (1200 g, 68%)