Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH3:22])[CH:3]([CH2:11][C:12]1[O:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=O.[BH4-].[Na+].C(OCC)(=O)C>CO.O>[CH2:20]([O:19][C:17]([C:14]1[O:13][C:12]([CH2:11][CH:3]([CH:2]([NH:1][CH2:33][C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=2)[CH3:22])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])=[CH:16][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)N)o1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)NCc2ccc3ccccc3c2)o1
Temperature: 0 °C
Yield: 76.5 %

Procedure:
500 mg of tert-butyl (2RS,3RS)-3-amino-2-{5-(ethoxycarbonyl)-2-furylmethyl}butanoate in 15 ml of methanol was stirred together with 251 mg of 2-naphthaldehyde at 50° C. for 2 hours under heating. The reaction solution was cooled to 0° C. and stirred with 61 mg of sodium borohydride at the same temperature for 15 minutes. Ethyl acetate and water were added to the reaction solution for extraction, and the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=6/1] to give 555 mg of the title compound as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]([CH3:15])=[C:13]([CH:16]=O)[N:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][CH2:19][O:20][CH2:21][CH3:22].C[O:24]CCOC>>[CH2:3]([N:10]1[C:14]([CH3:15])=[C:13]([CH:16]=[CH:18][C:19]([O:20][CH2:21][CH3:22])=[O:24])[N:12]=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCOC
Reactant: CCOCC
Reactant: Cc1c(C=O)ncn1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=Cc1ncn(Cc2ccccc2)c1C
Temperature: 10 °C

Procedure:
A suspension of 50% sodium hydride in mineral oil (1.03 g., 0.0215 mole) in dry 1,2-dimethoxyethane (50 ml.) is cooled to 10° C. and triethyl phosphonoacetate (4.82 g., 0.0215 mole) is added dropwise over 5 minutes under nitrogen atmosphere. The mixture is stirred at 10° to 20° C. for 3/4 hour. Then 1-benzyl-5-methyl-4-imidazolecarboxaldehyde (4.1 g., 0.02 mole) is added over 5 minutes and the mixture is stirred at room temperature for 13/4 hours. The reaction mixture is cooled in an ice bath and is diluted with 100 ml. of ether and 50 ml. of ice water. The organic layer is separated and extracted with cold 3 N hydrochloric acid (50 ml.). The acidic extract is neutralized with sodium bicarbonate and the product is extracted into ether. The ether extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product is an amber oil which solidifies to a yellow solid (5.4 g.). The crude ethyl 3-(1-benzyl-5-methyl-4-imidazolyl)-2-propenoate melts at 169°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH2:32]([OH:36])[CH2:33][CH2:34][OH:35].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:27][CH2:26][CH2:25][CH2:24][CH:32]([OH:36])[CH2:33][CH2:34][OH:35].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O-:28])=[O:27])=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C([O-])c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Product: OCCCC(O)CCO

Procedure:
A mixture of 2.25 g. of methyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 1,3-propanediol 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate.
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[N:17]=1.[O:27]1[CH2:32][CH2:31][CH2:30][O:29][CH:28]1[C:33]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=1>COC(C)(C)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[O:27]1[CH2:32][CH2:31][CH2:30][O:29][CH:28]1[C:33]1[CH:34]=[CH:35][C:36]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[N:14]=[N:15][N:16]([C:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[N:17]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2Cl)n1
Reactant: Br[Mg]c1ccc(C2OCCCO2)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C3OCCCO3)cc2)n1
Temperature: 0 °C

Procedure:
In another flask, dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) (0.022 g; 0.04 mmol) is suspended in tert-butyl methyl ether (3 mL) and cooled to about 0° C. before a 0.5 M solution of zinc chloride in tetrahydrofuran (0.40 mL; 0.20 mmol) and a solution of 5-(2-chloro-phenyl)-2-(1-methyl-1-phenyl-ethyl )-2H-tetrazole (1.20 g; 4.0 mmol) in tert-butyl methyl ether (1.2 mL) are added. To the vigorously stirred resulting suspension is added at about 0° C. 9.6 mL of the above 0.5 M 4-([1,3]dioxan-2-yl)phenylmagnesium bromide solution (4.8 mmol) over one hour. The resulting dark brown solution is allowed to warm up and further stirred at room temperature for 20 hours. The mixture is cooled to about 0° C., quenched with 10 mL of a 3.8% solution of ammonium chloride in water and diluted with ethyl acetate (25 mL). The aqueous phase is separated and extracted with ethyl acetate (25 mL). The combined organic phases are washed with a 0.5 M solution of sodium hydroxide in water (10 mL) and with a 10% solution of sodium chloride in water (10 mL). The combined organic phases are evaporated in vacuo. A solution of the resulting pale green solid in a small amount of ethyl acetate is filtered and evaporated. The resulting pale green solid is purified by column chromatography on silica gel eluting with a 1:10 mixture of tert-butyl methyl ether and toluene to afford 5-(4′-[1,3]dioxan-2-yl-biphenyl-2-yl)-2-(1-methyl-1-phenyl-ethyl)-2H-tetrazole as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[O:19])=[C:13]([F:28])[CH:12]=3)[C:3]=12.[ClH:42].[Cl:43]CCl>CC(C)=O>[ClH:43].[ClH:42].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[C:13]([F:28])[CH:12]=3)[C:3]=12
Reactant: ClCCl
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ncnc(N)c34)cc2F)c1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCNCC4)c4ncnc(N)c34)cc2F)c1
Temperature: 0 °C

Procedure:
tert-Butyl 4-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (117 mg, 0.209 mmol) was suspended in acetone (7 mL) and cooled to 0° C. Aqueous hydrochloric acid (6N, 1.6 mL) was slowly added to the reaction mixture. The reaction mixture was warmed to room temperature then heated at 50° C. for 4 hours. Concentration of the reaction mixture under reduced pressure followed by trituration with dichloromethane (25 mL) afforded N-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea dihydrochloride salt as an off-white solid (111 mg, 0.241 mmol). HPLC-RT: 11.98 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=461.3.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:45])[CH3:44])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[Cl:54]>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:45])[CH3:44])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[Cl:54])[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Clc1ccccc1CBr
Reactant: CC(=O)N[C@H]1CCN(c2nc(NC(C)(C)C)nc3[nH]nnc23)C1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(NC(C)(C)C)nc3nn(Cc4ccccc4Cl)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N—[(S)-1-(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-acetamide and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 443.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:57]3[CH2:58][CH2:59][CH:54]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=4[O:47][CH3:46])[CH2:55][CH2:56]3)=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCNCC1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C1CCN(C(=O)c2c(C)[nH]c3cc(Cl)ccc23)CC1
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 0.040 g (0.19 mmol) 6-chloro-2-methyl-1H-indole-3-carboxylic acid, 0.069 ml (0.40 mmol) N,N-diisopropylethylamine and 0.061 g (0.19 mmol) 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml dry N,N-dimethylformamide were added 0.038 g (0.20 mmol) 4-(2-methoxy-phenyl)-piperidine at room temperature. After stirring for 1 h the reaction mixture was quenched with 0.5 M aqueous sodium hydroxide solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.050 g; 69%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[C:10]([CH2:29][NH:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][C:10]=2[CH2:29][NH:30][CH3:31])[CH2:15][CH2:16]1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccc(F)cc2)CC1
Reactant: CC(=O)Cl
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(Cc2ccc(F)cc2)C(C)=O)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-(4-fluorobenzyl)-cyclohexylamine and acetylchloride. Colourless oil.
Reaction SMILES: [CH:1]1([CH:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[NH:9][C:8]([CH:19]([O:21][CH3:22])[CH3:20])=[C:7]2[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C>ClCCl.C1CCCCC1.C(OC(=O)C)C>[CH:1]1([C:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]=3[N:9]=[C:8]([CH:19]([O:21][CH3:22])[CH3:20])[C:7]=2[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(C)C1=C(C(=O)c2ccc(C(F)(F)F)cc2)C(C2CCCC2)C2=C(CC(C)(C)CC2=O)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)C2
Temperature: 0 °C

Procedure:
4.7 g 4-Cyclopentyl-2-(1-methoxy-ethyl)-7,7-dimethyl-3-(4-trifluoromethyl-benzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one are dissolved in 100 ml dichloromethane, cooled to 0° C. and 2.5 g 2,3-dichloro-5,6-dicyano-p-benzoquinone are added portionwise. The temperature is raised during 3 hours to room temperature. Then the volume is reduced to approximately 60 ml by evaporation in vacuo, the mixture is filtered and the filter cake is washed 5 times with 50 ml of dichloromethane. The combined organic phases are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 50:50). The product thus obtained is dissolved in cyclohexane/ethylacetate 70:30 and treated with charcoal. The mixture is filtered and the charcoal is washed 3 times with 100 ml cyclohexane/ethylacetate 70:30. The combined organic phases are evaporated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24](O)=[O:25].Cl.[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]>>[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][N:39]([C:24]([C:11]3[CH:12]=[N:13][C:14]4[N:15]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]=3[NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:25])[CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Reactant: Fc1ccc(C2CCNCC2)cc1F
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 70.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (220 mg, 0.62 mmol) obtained in step 2 and 4-(3,4-difluorophenyl)piperidine hydrochloride (WO2004/069798, 217 mg, 0.93 mmol), the title compound (232 mg, 70%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH3:19][N:2]([CH2:3][C:5]1([CH3:18])[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[O:6]1)[CH3:1]
Reactant: CN(C)C(=O)C1(C)Oc2ccccc2-n2cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CC1(C)Oc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the amide of formula 3, N,N,4-trimethyl-4H-pyrrolo-[2,1-c][1,4]benzoxazine-4-carboxamide (3 g), described in Example 15 in 50 ml of ether is added dropwise to a suspension of lithium aluminum hydride (1.5 g) in anhydrous ether (100 ml) over a period of 30 min. The reaction mixture is stirred at room temperature for 16 hr. Decomposition of the mixture with 6 ml of water gives a white precipitate, which is collected on a filter and washed with ether. The filtrate is extracted with 2% aqueous HCl. The extract is rendered basic with a 10% solution of NaOH and extracted with chloroform. The chloroform extract is dried (MgSO4), filtered and evaporated to give the title compound, nmr (DMSO-d6) δ 1.85 (s, 3H), 2.78 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[N:18]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O1CCCC1.O>[Br:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][N:18]=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a solution of 2-amino-5-bromo-4′-fluorobenzophenone (13.50 g, 45.9 mmol) in 6 N hydrochloride solution (400 mL) and tetrahydrofuran (500 mL) at −15° C. was slowly dropped a solution of sodium nitrite (4.12 g, 59.7 mmol) in water (20 mL). After stirring for 30 minutes in cold bath, to the reaction mixture was added a solution of tin(II) chloride dihydrate (28.48 g, 126 mmol) in concentrated hydrochloric acid (70 mL) dropwise. A white solid precipitated immediately. After 30 minutes, the white solid was filtered, dissolved in ethyl acetate, and washed with saturated sodium bicarbonate. The filtrate was neutralized with sodium hydroxide and extracted with dichloromethane. The ethyl acetate and dichloromethane layers were combined, dried over magnesium sulfate, and concentrated. Crystallization from ethyl acetate gave the title compound as a white solid (5.266 g). The mother liquor was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide another batch of the title compound (3.429 g, total 8.695 g, 65% yield). 1H NMR (CDCl3) δ 10.54 (br s, 1H), 8.11 (m, 1H), 7.87–7.92 (m, 2H), 7.50 (m, 1H), 7.34 (d, 1H), 7.20–7.26 (m, 2H); ES-MS (m/z) 293 [M+3]+, 291 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]([N:14]2[CH2:13][C@@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:24])[CH3:11])[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15]2)=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound 4-{(3R,4S)-3-(4-chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light-brown gum. MS m/e: 560.3 [M]+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:10][O:11][C:12]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:7][CH3:8])=[O:18])=[CH:15][CH:14]=1)=[O:22]
Reactant: COc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1ccc(C(=O)c2ccccc2OC)cc1
Temperature: 0 °C

Procedure:
To a mixture of anisole (216 g) and terephtalic acid-methyl ester-chloride (99 g) was added aluminium chloride (200 g) at 0° C. in an amount of 1/3 to 1/4 at a time. In that case, temperature was kept to 25° C. or less, and it took from 45 minutes to 1 hour for addition. The temperature returned to room temperature after 30 minutes from termination of addition, and after stirring for 1.5 hours to 2 hours, the pink colored precipitate was obtained by pouring ice-water. The precipitate was separated by filtration, dried with water and washed with methanol. Methanol washings were concentrated under reduced pressure, and washed with a small amount of methanol to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:4][N:3]=1.[CH2:23](N)[CH2:24][NH2:25]>CO>[NH:16]1[CH2:23][CH2:24][N:25]=[C:15]1[C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:11]([CH:20]([CH3:22])[CH3:21])=[C:10]([CH:17]=1)[O:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: NCCN
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C1=NCCN1

Procedure:
To a cooled (0° C.) suspension of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.138 g, 0.461 mmol) in dry methanol (15 ml) was bubbled with HCl gas for 10 minutes and refrigerated overnight. Solvent was evaporated under reduced pressure to give a yellow solid which was redissolved in dry methanol (10 ml). Ethylene diamine (0.034 ml, 0.509 mmol) was added and the reaction mixture was refluxed for 20 hours and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 7-50% methanol in methylene chloride/0.1% concentrated NH4OH) to yield 5-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-pyrimidine-2,4-diamine which was crystallized from methanol/ethyl acetate/ether as a white solid, (0.053 g, 33%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH:10]([C:15]2[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5][C:4]=1[C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[CH:35]([C:32]1[CH:31]=[CH:30][C:29]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH:10]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[CH:27][CH:28]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:8][C:3]=2[CH2:1][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1)([CH3:36])[CH3:37]
Reactant: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(C=O)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(CN2CCOCC2)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To the solution of 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid (240 mg, 0.48 mmol) and Morpholine (84 mg, 0.96 mmol) in dichloromethane (20 ml) is added NaBH(OAc)3 (143 mg, 0.67 mmol) and acetic acid (58 mg, 0.96 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography to afford 80 mg of the titled compound as a white solid. MS (ES): 573.5 [M+H]+.