Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1([CH:20]([CH3:24])[C:21](O)=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(Cl)Cl>[F:7][C:8]1([CH:20]([CH3:24])[C:21]([Cl:4])=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)C1(F)CC=CC=C1c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Cl)C1(F)CC=CC=C1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.8 g, 30 mmol) was combined with methylene chloride (30 mL). The resulting mixture was cooled to 0° C. and dimethylformamide (10 drops) was added. After 5 minutes of stirring a solution of 2-fluoro-α-methyl-biphenylacetic acid (3.0 g, 12 mmol) in methylene chloride (30 mL) was added dropwise over a 30 minute period. The reaction mixture was allowed to warm to room temperature and stirred overnight The solvent was evaporated to give the product in a quantitative yield as a yellow solid. 1H NMR (CDCl3) δ: 1.58 (d, 3 H), 4.20 (q, 1 H), 7.11 (t, 2 H), 7.33-7.47 (m, 4 H), 7.54 (d, 2 H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[C:10]1([CH:16]([CH2:19][CH3:20])[C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([CH:16]([CH2:19][CH3:20])[C:17]#[N:18])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: CCC(C#N)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCC(C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A 3-necked round-bottomed flask was charged with conc. HNO3 (240 ml) and cooled to 10° C. with the aid of an ice/acetone bath. Conc. H2SO4 (240 ml) was then added slowly so as to maintain the temperature below 30° C. 2-Phenylbutyronitrile (Aldrich, 110 ml) was introduced dropwise to the stirred solution over a period of 1 hour, maintaining the temperature below 20° C. The ice/acetone bath was then removed and the mixture stirred for a further 30 minutes at ambient temperature before pouring it onto crushed ice (100 g). The resulting mixture was extracted with ethyl acetate (1500 ml×2) and the extracts pooled, washed with saturated bicarb. (1000 ml) and water (500 ml). After drying over MgSO, the ethyl acetate was evaporated under reduced pressure to give crude 2-(4-nitrophenyl)butyronitrile as a yellow oil, crude yield 138 g, 98%. Analysis by GC.MS indicated a para:meta ratio of 3.5:1.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]Br)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[OH:19][CH:20]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>C(#N)C>[OH:18][C:5]1[C:6]([CH2:15][CH2:16][CH3:17])=[C:7]([O:8][CH2:9][CH2:10][CH2:11][O:36][C:33]2[CH:32]=[CH:31][C:30]([CH:20]([OH:19])[CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:35][CH:34]=2)[CH:13]=[CH:14][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: Oc1ccc(C(O)CCCc2ccccc2)cc1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(O)CCCc3ccccc3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
To a solution of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide (J. Med. Chem. 29, 1573-1576, 1986) (315 mg) and the phenol of Step 1 (242 mg) in acetonitrile (5 mL) was added cesium carbonate (650 mg) and the mixture was heated to reflux for 5 hrs. The suspension was cooled to 25° C. and poured into 25% aqueous NH4OAc and EtOAc. The organic layer was washed with brine, dried with MgSO4 and the solvents are removed in vacuo. The residue was purified by chromatography on silica gel using EtOAc and hexanes (1:2) to yield the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].[CH2:35]([CH2:37][NH2:38])[OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([NH:38][CH2:37][CH2:35][OH:36])=[O:24])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)NCCO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.67 h
Yield: 47 %

Procedure:
To a solution of 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (for a preparation see Intermediate 10)(44 mg, 0.097 mmol) and ethanolamine (0.012 mL, 0.194 mmol) in DMF (3 mL) were added HATU (55.2 mg, 0.145 mmol) and DIPEA (0.051 mL, 0.290 mmol). The resulting mixture was stirred for 40 min, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3), the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(2-hydroxyethyl)propanamide (22.8 mg, 47%) as a, viscous yellow oil. LCMS (Formate, 2 min), Rt=0.80 min, MH+=498.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][C:8]2[C:9]3[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=3[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:9]3[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=3[S:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:17][CH:18]=2)=[CH:31][CH:32]=1
Reactant: N#Cc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
3-(4-Cyanobenzyl)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (50 mg, 0.114 mmol) in THF (2 mL) was treated with lithium aluminum hydride (40 mg) at ambient temperature under argon for 1 h. The reaction was quenched with water (0.5 mL) and a solution of NaOH (1.0 M, 0.5 mL). The stirring was continued for 15 min. The resulting mixture was diluted with brine (30 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (10:40:50) afforded the product (19 mg, 37%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][N:11]2[C:15](=[O:16])[C:14]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:13][C:12]2=[O:22])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:41]([CH:50]=O)[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:43][C@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:41]([CH2:50][N:19]2[CH2:18][CH2:17][C:14]3([NH:13][C:12](=[O:22])[N:11]([CH2:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:24][CH:23]=4)[C:15]3=[O:16])[CH2:21][CH2:20]2)[CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Reactant: CS(=O)(=O)c1ccc(CN2C(=O)NC3(CCNCC3)C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](CN2CCC3(CC2)NC(=O)N(Cc2ccc(S(C)(=O)=O)cc2)C3=O)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To 187 mg (0.50 mmol) of 3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride was added 5 mL of DCM followed by 0.066 mL of triethylamine (0.50 mmol) and a solution of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.93 mL of a 148 mg/mL solution, 0.50 mmol). The solution was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride was added (159 mg, 0.75 mmol). The solution was stirred overnight. The resulting mixture was evaporated to dryness and purified by chromatography on Bond Elute™ (10 g) using 1:1 EtOAc:Hexane followed by 1% methanol in DCM. After evaporation of the desired fractions, 93 mg (31%) of (3S,4S)-3-[3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid were obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH2:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[NH2:32][NH2:33]>C(O)C.O>[CH2:25]([C:13]1[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15]2[C:11]([C:12]=1[CH2:27][C:28]([NH2:30])=[O:29])=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([NH:32][NH2:33])=[O:3])=[CH:17][CH:16]=2)[CH3:26]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1c(CC(N)=O)c2cc(OCCCC(=O)NN)ccc2n1Cc1ccccc1
Yield: 87 %

Procedure:
A mixture of 211 mg (0.05 mmol of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1 mL of hydrazine in 5 mL of ethanol was heated to maintain reflux for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was stirred with MeOH and the insoluble material filtered to give 177 mg (87% yield) of 2-ethyl-5-(4-hydrazino-4-oxobutoxy)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 176°-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCNCC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCNCC4)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 11.4 %

Procedure:
To a solution of compound methyl 6-chloro-5-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added aq. NaOH (2 mL, 1.0 N). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (10 mg, 11% yield) as a white solid. MS (ES+) 400.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.00 (S, 1 H), 8.35 (s, 1 H), 8.05 (s, 1 H), 7.95 (s, 1 H), 7.60 (s, 1 H), 7.35 (d, 2 H), 7.00 (m, 2 H), 4.10 (m, 2 H), 2.90 (m, 4 H), 2.70 (m, 2 H), 2.60 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Cl:27][CH2:28][C:29]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[C:2]([F:1])[CH:7]=2)[CH2:9][CH2:10]1)=[O:30]
Reactant: Fc1cc(N2CCNCC2)ccc1-c1ncccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Fluoro-4-piperazin-1-yl-phenyl)-pyrimidine (5AB) (889 mg, 3.442 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (5 mL) and triethylamine (697 mg, 959 uL, 6.884 mmol, 2 equiv) was added, followed by slow addition of a solution of chloroacetyl chloride (6AB) (466.5 mg, 330 uL, 4.13 mmol, 1.2 equiv) in tetrahydrofuran at room temperature. The mixture was then stirred for about 1 hour at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[CH2:11]O.[Li+].[Cl-].S(Cl)([Cl:17])=O.O>CN(C)C=O>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([S:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(SC)cc1CO
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SC)cc1CCl
Reaction time: 0.25 h

Procedure:
To a solution of Example 170B (1.23 g, 6.69 mmol) in 15 mL of N,N-dimethylformamide was added LiCl (567 mg, 13.4 mmol), then 2 mL (27 mmol) of thionyl chloride. The solution warmed spontaneously on addition of the thionyl chloride. After 15 min, 50 mL of water was added, then the aqueous suspension was extracted with diethyl ether (3×15 mL). The combined organic layers were back extracted with water (1×15 mL), saturated NaHCO3(aq.) (2×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated in vacuo to 1.24 g (92%) of an oil. This was used in the next step on the same day and without further purification.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][C:7]1[C:15]([CH3:17])([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH+:8]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](=O)[CH3:29])=[CH:22][CH:21]=1>CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:29][C:28]1[N+:8]2[C:9]3[C:14]([C:15]([CH3:17])([CH3:16])[C:7]=2[CH:6]=[C:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)[CH:27]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1=[NH+]c2ccccc2C1(C)C
Reactant: COc1ccc(C=CC(C)=O)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: COc1ccc(-c2cc(C)[n+]3c(c2)C(C)(C)c2ccccc2-3)cc1

Procedure:
2,3,3-Trimethyl-3H-indolium perchlorate (5 g.) and 4-p-methoxyphenylbut-3-ene-2-one (10 g.) were heated together on the steam bath for three hours. The cooled mixture was diluted with methanol and filtered. The product was purified by recrystallization from acetonitrile. Yield 4.1 g.; m.p. 298°-300° .
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].Cl[CH2:30][C:31](Cl)=[O:32].[H-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[C:31](=[O:32])[CH2:30][O:28][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OCC2=O)cc1

Procedure:
Prepared by analogy to Example 74a by reaction of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (diastereomer B), chloroacetyl chloride and sodium hydride, and purification of the base on a silica gel column using toluene/ethyl acetate=6:4 as eluant.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B using 1-(4-tert-butylphenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 435.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C(=O)(O)[O-].[Na+]>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.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:21]=[O:22])[CH:28]=3)=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
In a sealed pressure tube was added 4-bromo-2-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (2.1 mmol; preparation disclosed in WO03/000690A1), 3-formylbenzeneboronic acid (2.1 mmol), N,N-dimethylformamide (15 mL), aqueous saturated sodium bicarbonate (5 mL) and tetrakis(triphenylphosphine)palladium(0) (0.1 mmol). The reaction was purged with nitrogen, capped and stirred at 100° C. for 16 h. After cooling to room temperature the reaction was concentrated under vacuum, taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. Purification by flash chromatography by silica gel (0-4% ethyl acetate in methylene chloride) gave the title compound as a white solid (77%). ESMS [M+H]+: 441.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[CH:19]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:18][CH2:17]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(=[O:34])C>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:30])([F:31])[F:29])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[CH:19]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH2:18][CH2:17]4)[C:10]2=[O:34])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)O
Reactant: CCC(=O)NC1CCc2cc(N3CCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(=O)NC1CCc2cc(N3CCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3=O)ccc21
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a solution of 235.7 mg N-{5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2,3-dihydro-1H-inden-1-yl}propanamide (0.5 mmol) in 20 ml toluene was added 1304 mg manganese(IV)dioxide (15.0 mmol) and stirred at 20° C. for 12 h. After standing for about 2 d at room temperature 100 μl acetic acid were added and the mixture stirred for 15.5 h. The reaction mixture was filtered through celite-silica gel. The crude product (198 mg) was subjected to silica gel column chromatography yielding 20 mg of compound (I-A-2) and 67 mg pure N-{5-[3-(3,5-dichlorophenyl)-2-oxo-3-(trifluoromethyl)pyrrolidin-1-yl]-2,3-dihydro-1H-inden-1-yl}propanamide (I-B-2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:12])[N:8]([C:18]3[CH:17]=[C:16]([Cl:21])[N:15]=[C:14]([NH2:13])[N:19]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1Cc2ccc(Br)cc2CN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Product: CC1Cc2ccc(Br)cc2CN1c1cc(Cl)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 7-bromo-3-methyl-1,2,3,4-tetrahydroisoquinoline and 2-Amino-4,6-dichloropyrimidine (Alfa Aesar, Cat. No. A11330). LCMS (M+H)+: m/z=353.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([CH2:38][C:39]6[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=6)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([CH2:38][C:39]6[CH:40]=[CH:41][C:42]([NH2:45])=[CH:43][CH:44]=6)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc([N+](=O)[O-])cc6)cc5)cc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cc2ccc(Cc3ccc(Cc4ccc(Cc5ccc(Cc6ccc(N)cc6)cc5)cc4)cc3)cc2)cc1

Procedure:
In a 1-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 16.4 g of 1,1-bis(4-(4-(4-nitrophenylmethyl)phenylmethyl)phenyl)methane was dissolved in 500 milliliters of tetrahydrofuran, 1.7 g of a Pd-C catalyst (a 5% product, containing 54.8% of water) was added and contacted with hydrogen gas while cooled with water at a normal pressure and then stirred. After absorption of hydrogen was stopped, the catalyst was filtered off and the objective product adhered to a residual layer of the catalyst was washed with chloroform thoroughly and then the filtrate was concentrated. By recrystallizing the concentrate from a chloroform solvent, 11.0 g of a diamino compound according to the invention, that is, 1,1-bis(4-(4-(4-aminophenylmethyl)phenylmethyl)phenyl)methane was obtained as crystals. Melting point was from 192.0° to 193.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](O)(=[O:13])[C:10](O)=[O:11]>Cl>[NH:8]1[C:10](=[O:11])[C:9](=[O:13])[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]1=2
Reactant: Nc1ccncc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2ccncc2[nH]c1=O
Yield: 81.1 %

Procedure:
To a suspension of 3,4-diaminopyridine (10 g, 0.068 mol) in 4N aqueous HCl (100 ml) is added oxalic acid (10.4 g, 0.082 mol) and the reaction mixture is refluxed for 20 h. The reaction mixture is cooled down and the solid precipitated is filtered, washed with water then dried under vacuum to afford 9 g (80%) of the title compound as a solid. HPLC (max plot) 98%. LC/MS: (ES+): 164.3.