Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].Cl.[N:7]1([CH2:12][CH:13]([N:15]2[C:28]3[CH:27]=[C:26]([C:29]([NH2:31])=[NH:30])[CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH3:14])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)C.ClCCCl>[CH3:4][C:3]1[N:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]3[S:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH:13]([CH3:14])[CH2:12][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[C:28]=3[CH:27]=2)[NH:31][CH:2]=1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Reactant: CC(=O)CCl
Agent: Cl
Solvent: ClCCCl
Solvent: CCO
Product: Cc1c[nH]c(-c2ccc3c(c2)N(C(C)CN2CCCC2)c2ccccc2S3)n1

Procedure:
Chloroacetone (0.44 cc) and 4 A molecular sieve (1 g) are added to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (1.76 g) in dry ethanol (17 cc). The suspension is maintained under reflux for 20 hours. After cooling, the suspension is filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is diluted in 1,2-dichloroethane (200 cc). The organic phase is washed with distilled water (3×100 cc) and then with saturated sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is purified by chromatography on a column (height: 15 cm; diameter: 2.4 cm) of silica (0.04-0.06 mm), eluting with a 90:10 (by volume) mixture (800 cc) of 1,2-dichloroethane and methanol and collecting 50-cc fractions. The first 300 cc of eluate are discarded and fractions 4 to 10 are concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 2-(4-methyl-2-imidazolyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]phenothiazine(0.33g) in the form of a golden yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]([NH2:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]([NH:19][S:33]([C:31]1[S:32][C:28]([Cl:27])=[CH:29][CH:30]=1)(=[O:35])=[O:34])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)C(N)c1nccn1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1nccn1Cc1ccccc1
Reaction time: 3.5 h
Yield: 59 %

Procedure:
To a stirred solution of [1-(1-benzyl-1H-imidazol-2-yl)-2-ethylbutyl]amine (448 mg, 1.74 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.36 mL, 2.6 mmol) and 5-chlorothiophene-2-sulfonylchloride (453 mg, 2.09 mmol). The mixture was stirred for 3.5 h and then diluted with EtOAc, washed twice with 1N HCl, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, CHCl3, then 1% MeOH/CHCl3 to 2% MeOH/CHCl3) to yield a white solid in 59% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([OH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1C2=C(CCCC2)C(O)N1c1ccc(Cl)cc1F
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In 400 ml of ethanol was dissolved 40.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1,3-dione, and 2.4 g of sodium borohydride was added to the solution with stirring over a 30-minute period, while cooling was effected suitably so as to maintain the reaction temperature at 20° to 30° C. After stirring was further continued at room temperature for 1 hour, the reaction mixture was neutralized with dilute acetic acid and concentrated to about one third of the original volume, followed by cooling. The resulting crystals were collected by filtration, washed with water and dried, thereby affording 36.2 g (yield of 90%) of the subject compound. Recrystallization from ethyl acetate yielded white crystals, m.p. 178°-179° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>C1COCC1>[NH2:19][C:11]1[CH:12]=[CH:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:18])[C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=c1c([N+](=O)[O-])c(Cl)ccn1Cc1ccccc1
Reactant: N
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Yield: 91.4 %

Procedure:
A solution of 1-benzyl-4-chloro-3-nitro-1H-pyridin-2-one (1.30 g, 4.91 mmol) and 28% aqueous ammonia (4.92 g, 39.3 mmol) in THF (30 mL) was stirred at room temp for 17 h. The solvent was evaporated under reduced pressure and water was added to the residue. The resulting precipitate was collected by filtration, and washed with water to give 4-amino-1-benzyl-3-nitro-1H-pyridin-2-one (1.10 g, 91% yield). 1H-NMR (DMSO): δ 8.13 (m, 2H), 7.69 (d, 1H, J=8.0 Hz), 7.31 (m, 5H), 5.94 (d, 1H, J=8.0 Hz), 4.96 (s, 2H). MS: calculated for C12H11N3O3+H 246.1; found: 246.2.
Reaction SMILES: [OH:1]O.[CH3:3][S:4][C:5]([S:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8]>C(O)(=O)C>[CH3:3][S:4]([C:5]([S:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8])=[O:1]
Reactant: OO
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC(=O)O
Product: CSC(=C[N+](=O)[O-])S(C)=O
Reaction time: 17 h

Procedure:
Hydrogen peroxide (30%, 100 volume, 113 ml) was added over 15 minutes to a stirred solution of 1,1-bis-methylthio-2-nitroethylene (165 g) in acetic acid (4,500 ml) at 60°, and the mixture was stirred at 60° for 17 hours. The mixture was evaporated to a residue which was crystallised from butanone to give the title product as a mixture of the "Z" and "E" isomers m.p. 137°-143°. Further recrystallisation gave one isomer 145°-148° and the mother liquors were evaporated to a residue which was recrystallised from dimethoxymethane to give the other isomer m.p. 90°-93°.
Reaction SMILES: C(OC([N:11]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1)[CH2:12][C:13]([NH:15]CC(N)=O)=O)=O)C1C=CC=CC=1.C[OH:29]>[Pd]>[CH3:26][C:24]1[CH:23]=[C:22]([CH3:27])[N:21]=[C:20]([NH:11][C:12](=[O:29])[CH2:13][NH2:15])[CH:25]=1
Reactant: CO
Reactant: Cc1cc(C)nc(N(CC(=O)NCC(N)=O)C(=O)OCc2ccccc2)c1
Agent: [Pd]
Product: Cc1cc(C)nc(NC(=O)CN)c1

Procedure:
1 g (2.6 mmol) of the product of Example 24 is dissolved in 60 ml of methanol. Palladium-on-carbon is added and the whole is stirred under a hydrogen atmosphere. Filtration is then carried out, the methanol is evaporated and the title product is recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4C(O)=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1(P([N:50]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH2:50])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C(=O)O)cc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3N)cc2)cc1
Yield: 55.2 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-carboxyphenyl)benzamide (232 mg), diphenylphosphoryl azide (151 mg), and triethylamine (0.084 ml) in benzene (10 ml) was refluxed for 5 hours and 1N hydrochloric acid (4 ml) was added to the solution. The mixture was refluxed for 4 hours and the mixture was washed with aqueous saturated sodium hydrogen carbonate and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-aminophenyl)benzamide (120 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:20])([CH3:1])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:19])[N:6]=1)=[O:4]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCNCCC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCN(CCC(C)C)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 17.3 mg N-ethyl-iso-amylamine, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 60-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound. LC-MS: 4.16 min. (m/Z=388.3, 4.10.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:29][CH2:30][C:31]([OH:33])=[O:32])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}glycinate (D89) (20 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 50° C. for 3 h. The mixture was cooled to room temperature and acidified with aqueous HCl (2 M) to pH 4-5. The mixture was partitioned between ethyl acetate (25 mL) and water (20 mL). The organic phase was evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}glycine (E64) (13 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.10 (2H, t), 3.24 (2H, t), 3.65 (3H, s), 3.87 (2H, s), 4.88 (1H, m), 7.22 (1H, t), 7.30 (1H, s), 7.45 (1H, d), 7.47 (1H, dd), 7.83 (1H, dd), 8.12 (1H, dd), 8.18 (1H, d). MS (ES): C24H26ClN4O4 requires 468; found 469.2 (M+H+).
Reaction SMILES: [CH3:1][SiH:2]([O:5][CH3:6])[O:3][CH3:4].[CH2:7]([Cl:11])[C:8](=[CH2:10])[CH3:9]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru]>[Cl:11][CH2:7][CH:8]([CH3:9])[CH2:10][Si:2]([CH3:1])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CO[SiH](C)OC
Reactant: C=C(C)CCl
Agent: [Ru]
Agent: [C-]#[O+]
Product: CO[Si](C)(CC(C)CCl)OC
Temperature: 80 °C
Yield: 69.7 %

Procedure:
The procedure of Example 3 was repeated using 30.1 g of methyldimethoxysilane (1.15 equiv.), 0.0030 g of Ru3 (CO)12 (27 ppm of Ru), and 22.7 g of methallyl chloride (MAC). The MAC was added dropwise to the reactor containing the methyldimethoxysilane over 2 hours at 60° C., followed by heating the reaction mixture at 80° C. for 19 additional hours. Vacuum distillation at 5° C./22 mm provided 34.4 g (63% yield) of 3-chloro-2-methylpropylmethyldimethoxysilane. This example demonstrates that good yields are obtained when MAC is substituted for AC, and methyldimethoxysilane is substituted for TMS, in the absence of inert solvent and using only 27 ppm of Ru.
Reaction SMILES: Br[CH2:2][C:3](OC)([CH3:6])[CH2:4][OH:5].[Na].[CH2:10]([SH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CO>C(O)C>[CH2:6]=[C:3]([CH2:2][S:28][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][OH:5]
Reactant: COC(C)(CO)CBr
Reactant: CCCCCCCCCCCCCCCCCCS
Agent: [Na]
Solvent: CO
Solvent: CCO
Product: C=C(CO)CSCCCCCCCCCCCCCCCCCC

Procedure:
3-Bromo-2-methoxy-2-methylpropan-1-ol is reacted with the sodium salt of octadecanethiol in ethanol. The 2-methylene-3-octadecylthiopropan-1-ol (wax-like substance) is thereby obtained with the splitting off of methanol.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][C:29]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[N:28][CH:27]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(C(=O)N4Cc5cccn5Cc5ccccc54)cc3)cn2)CC1

Procedure:
using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 5 ml of N-methylpiperazine gives 1 g of the desired product :M+ =500.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[OH-].[NH4+:32]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:32])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol) in toluene (4.8 mL) and N,N-dimethylformamide (12 μL) at 25° C. was treated with a 2.0 M solution of oxalyl chloride in methylene chloride (0.36 mL, 0.73 mmol). This solution was stirred at 25° C. for 30 min. At this time, the reaction was cooled to −60° C. and treated dropwise with a 30% aqueous ammonium hydroxide solution (0.59 mL, 5.24 mmol). The resulting suspension was allowed to gradually warm to 25° C. and stirred at 25° C. for 1 h. The reaction mixture was then extracted with ethyl acetate (3×25 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage Flash 40S column, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (175 mg, 88%) as a colorless oil: [α]23589=−45.8° (c=0.096, chloroform); EI-HRMS m/e calcd for C15H20ClNO3S (M+) 329.0852, found 329.0851.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[N:22][C:23](SC)=[N:24][CH:25]=2)[N:20]1[C:31]1[N:36]=[C:35]([N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]2=[O:43])[CH:34]=[CH:33][CH:32]=1)[CH:17]=[CH2:18]>>[CH2:16]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[N:22][C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]4)=[CH:4][CH:3]=3)=[N:24][CH:25]=2)[N:20]1[C:31]1[N:36]=[C:35]([N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]2=[O:43])[CH:34]=[CH:33][CH:32]=1)[CH:17]=[CH2:18]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(-n2ccccc2=O)n1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CC[C@@H](N(C)C)C4)cc3)nc2n1-c1cccc(-n2ccccc2=O)n1

Procedure:
The entitled compound was obtained as a yellow solid (35.5 mg) in the same manner as in Production Example 12-2, for which, however, (3R)-1-(4-aminophenyl)-N,N-dimethylpyrrolidin-3-amine was used in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Production Example 12-2, and 6′-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one was used in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Ni]>[C:1]1([CH2:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:19])([F:20])[F:21])[CH:12]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Ni]
Solvent: CCO
Product: NCC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reaction time: 42 h
Yield: 91.8 %

Procedure:
To a solution of 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)-propanenitrile (2.20 g, 4.88 mmol), prepared as described in Procedure 15, in EtOH (45 mL) was added an aqueous slurry of Raney 2800 nickel (4 mL). The reaction mixture was stirred under an atmosphere of hydrogen (70 psi) for 42 h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)propan-1-amine (2.04 g, 92% yield) as a clear, colorless oil. LCMS: RT=1.87 min [M+H] 456.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.21 (s, 2 H), 3.45 (s, 2 H), 6.59 (d, J=7.03 Hz, 2 H), 6.92 (s, 2 H), 7.01-7.15 (m, 7 H), 7.31 (t, J=8.13 Hz, 2 H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[CH2:12][C:13]3[CH:18]=[N:17][C:16]([S:19][CH3:20])=[N:15][C:14]=3[N:21]([CH3:24])[C:22]=2[OH:23])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-c2cc3cnc(SC)nc3n(C)c2=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C)C(O)=C(c1cc(CO)ccc1C)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
4-Methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester (150 mg, 0.422 mmol) was dissolved in 6 mL dry THF. The reaction mixture was cooled to 0° C., and LAH (0.63 mL of 1.0 M solution in THF, 0.633 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 minutes, and then the ice bath was removed. Water (0.3 mL) in 2 mL THF was added dropwise. After stirring for 10 minutes, 0.3 mL of 20% aqueous NaOH was added. After stirring for another 10 minutes, 0.8 mL water was added. The reaction mixture was stirred for 90 minutes, then filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give 132 mg of 6-(5-Hydroxymethyl-2-methyl-phenyl)-8-methyl-2-methylsulfanyl-5,8-dihydro-pyrido[2,3-d]pyrimidin-7-ol, MS (M+H)=330.
Reaction SMILES: O[C:2]1([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[CH2:16][OH:17])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.Cl>>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]2([C:9]3[C:10](=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[CH2:16][O:17]2)[CH2:7][CH2:6]1
Reactant: Cc1ccc(C2(O)CCN(C)CC2)c(CO)c1
Agent: Cl
Product: Cc1ccc2c(c1)COC21CCN(C)CC1

Procedure:
Treatment of 4-hydroxy-4-(α-hydroxy-5-methyl-2-tolyl)-1-methylpiperidine with hydrochloric acid by the method described in Example 16d provides 1,3-dihydro-1',5-dimethylspiro[isobenzofuran-1,4'-piperidine].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.IC1C=C(C2C=CC(C(F)(F)F)=CC=2)C=C(C(F)(F)F)N=1.[Br:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1>>[Br:43][C:44]1[CH:49]=[C:48]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nc(C(F)(F)F)c2)cc1
Reactant: OB(O)c1cccc(Br)c1
Agent: FC(F)(F)c1ccc(-c2cc(I)nc(C(F)(F)F)c2)cc1
Product: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from a mixture of 2-chloro-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.26) (65%) and 2-iodo-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.49) (35%) (5.5 g, 4.62 mmol) and commercially available 3-bromo-benzene-boronic acid (1.02 g, 5.1 mmol) according to the general procedure IVb. Obtained as a white solid (1.43 g, 69%). MS (ISP) 446.0 [(M+H)+] and 448 [(M+2+H)+]
Reaction SMILES: [CH3:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH3:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH:10][C:26](=[O:27])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc2c(c3c1CCC3)OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(c3c1CCC3)OC(CNC(=O)OCc1ccccc1)C2
Yield: 107.2 %

Procedure:
Treatment of (±)-1-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (2.28 g, 11.2 mmol) with diisopropylethylamine (2.16 g, 16.7 mmol) followed by benzyl chloroformate (2.19 g, 12.8 mmol) generally according to the procedure described for Intermediate 15 gave 4.05 g (81%) of (±)-benzyl (5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as a white solid. Rf=0.33 (silica, ethyl acetate:hexanes 1:4); mp 109-113° C.; Anal. calcd. for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.42; H, 6.91; N, 4.10. Chiral HPLC separation of (±)-benzyl (5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (Chiralcel OJ, methanol) provided two fractions. Fraction 1 (Rt=19.001 min, Chiralcel OJ, methanol); Fraction 2 (Rt=23.125 min, Chiralcel OJ, methanol).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].C(=O)([O-])[O-].[La+3:13].C(=O)([O-])[O-].C(=O)([O-])[O-].[La+3]>O>[O-:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4].[La+3:13].[O-:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4].[O-:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [La+3]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F
Yield: 204.7 %

Procedure:
40 ml of H2O are placed in a 100 ml round-bottomed flask having a magnetic stirrer, and 12.78 g (85 mmol) of trifluoromethanesulfonic acid are weighed in. With stirring, 14.15 g (15 mmol) of lanthanum carbonate are added. The neutral suspension is filtered, and the filtrate is concentrated by evaporation in a rotary evaporator and then dried under a high vacuum. 18.0 g of lanthanum triflate are obtained in the form of a white powder.