Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:31][CH3:32])[C:9]([C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C@@H:13]([CH3:30])[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:39]([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45]Br)[CH3:40]>CN(C)C=O>[CH2:39]([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:11]([C:9](=[O:10])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:31][CH3:32])[CH2:12][C@@H:13]2[CH3:30])=[O:29])=[CH:27][CH:26]=1)[CH3:40].[CH2:39]([O:41][C:42](=[O:47])[CH2:43][CH2:44][CH2:45][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:11]([C:9](=[O:10])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:31][CH3:32])[CH2:12][C@@H:13]2[CH3:30])=[O:29])=[CH:27][CH:26]=1)[CH3:40]
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@@H](C(=O)N(CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Product: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](C(=O)N(CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
(±)-trans-1-(4-Hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (585 mg, 1.30 mmol) was dissolved in dimethylformamide (20 mL). Potassium carbonate (1.5 g) was added, followed by ethyl-4-bromobutyrate (2.53 g, 1.9 mL, 13 mmol). The reaction was warmed to 90° C. and stirred under nitrogen overnight. Upon completion, the reaction was cooled to room temperature. The solvent layer was decanted and concentrated. The residue was dissolved in ethyl acetate. The residual solids in the reaction flask were washed with ethyl acetate and the washings combined with the filtrate ethyl acetate solution. The combined ethyl acetate layers were washed with water (3×) and brine, dried over sodium sulfate, filtered, and concentrated to afford the crude product. The crude material was a mixture of cis and trans isomers due to racemization under the alkylation conditions. The mixture was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to afford pure (±)-trans-4-(4-{4-[(4-chloro-phenyl)-ethyl-carbamoyl]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester as a foam (88%) and pure (±)-cis-4-(4-{4-[(4-Chloro-phenyl)-ethyl-carbamoyl]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester. Data for the trans isomer: 1H-NMR (CDCl3) δ: 0.97 (d, 3H), 1.13 (t, 3H), 1.24 (t, 3H), 1.73 (ddd, 1H), 2.01-2.14 (m, 2H), 2.41-2.59 (m, 3H), 3.61-4.00 (m, 5H), 4.06-4.18 (m, 2H), 5.01-5.14 (m, 1H), 6.44 (d, 1H), 6.68-6.84 (m, 4H), 6.89 (dd, 1H), 7.16-7.27 (m, 2H), 7.42-7.51 (m, 4H). MS m/z: 563 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][C:14]([C:28]3[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=3)=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:18]=3)[N:16]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH2:39]([O:41][C:42]([N:44]=[C:45]=[O:46])=[O:43])[CH3:40].CO>C(Cl)(Cl)Cl>[CH2:39]([O:41][C:42]([NH:44][C:45]([N:13]1[C:14]([C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=2)=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:21][CH:22]=2)[N:16]=[C:12]1[C:5]1[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:46])=[O:43])[CH3:40]
Reactant: CCOC(=O)N=C=O
Reactant: CCN(CC)c1ccc(-c2nc(-c3cc(OC)c(O)c(OC)c3)[nH]c2-c2ccc(N(CC)CC)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=O)n1c(-c2cc(OC)c(O)c(OC)c2)nc(-c2ccc(N(CC)CC)cc2)c1-c1ccc(N(CC)CC)cc1
Reaction time: 5 h
Yield: 61.3 %

Procedure:
In 20 ml of chloroform, 0.8 g of 2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis(4-diethylaminophenyl)imidazole obtained in Example 1 (2) was dissolved. Then, 0.7 g of ethoxycarbonyl isocyanate (mfd. by Aldrich Chemical Co. Inc.) was added to the resulting solution and the reaction was carried out at room temperature for 5 hours with stirring. After the reaction, 5 ml of methanol was added to the reaction solution to decompose excess ethoxycarbonyl isocyanate, followed by removal of the solvent by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: a mixed solvent of ethyl acetate and n-hexane) to give 0.6 g of green crystals of 1-(ethoxycarbonylaminocarbonyl)-2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis(4-diethylaminophenyl)imidazol having a m.p. of 60° C.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]=O)[CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:46])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:46])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:42][C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N[C@@]1(C(=O)O)CN(Cc2cccnc2)C[C@@H]1CCCB(O)O
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (175 mg, 0.443 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and pyridine-3-carboxaldehyde (75 mg, 0.70 mmol), stirred for 2 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 20 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carboxylic acid (115 mg, 68%) as a white semisolid. NMR (d6-DMSO) δ 8.90 (m, 1 H), 8.74 (m, 1 H), 8.00 (m, 1 H), 7.12 (m, 1 H), 4.55-4.85 (m, 2 H), 3.10-4.00 (m, 3 H), 2.70-3.00 (m, 1 H), 1.70 (m, 2 H), 0.90-1.50 (m, 3 H), 0.55-0.70 (m, 2 H). MS (m+1): 308.4; MS (m−H2O+1): 290.4.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4cccc(Cl)c4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 45.8 mg (0.269 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 73.3 mg (55% of theory).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10](OCC)(OCC)[CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=1)[CH3:2].Cl.[C:20](=[NH:25])(OCC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[N:25]=[C:20]([CH3:21])[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOC(C)=N
Reactant: CCNc1cc(C(CN)(OCC)OCC)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNc1cc(-c2c[nH]c(C)n2)ccn1

Procedure:
A mixture of 2.0 g. (8 mmoles) of 2-(2-ethylamino-4-pyridyl)-2,2-diethoxyethylamine, 1.0 g. (8.3 mmoles) of ethyl acetimidate hydrochloride and 30 ml. of absolute ethanol was heated at reflux for 1.3 hours. The mixture was concentrated, and the residue taken up in 10 ml. of concentrated hydrochloric acid. The acid solution was heated on a steam bath for one hour and the cooled reaction made basic by the addition of solid potassium carbonate. The product was extracted with chloroform (4×15 ml.) and the combined extracts dried and concentrated to give 1.1 g. of crude product. The product was chromatographed over 35 g. of silica gel using chloroform-methanol (19:1, v:v) as the eluent to give 510 mg. (30%), m.p. 214°-216° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:13](=[O:14])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])[CH:6]=[N:7]2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)C(Cc1ccccc1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(Cc2ccccc2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 57 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionic acid (Intermediate 30) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionamide as a light yellow solid (1.07 g, 57%); ES+-HRMS m/e calcd for C30H35N5O4SiF2 [M+H+] 596.2499 found 596.2499. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.06 (s, 6H) 0.80 (s, 9H) 3.36-3.50 (m, 2H) 3.86 (t, J=5.1 Hz, 2H) 4.08 (t, J=5.1 Hz, 2H) 5.75-5.88 (m, 1H) 5.93 (d, J=2.7 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.06-7.53 (m, 8H) 7.56 (d, J=2.1 Hz, 1H) 8.25 (d, J=2.7 Hz, 1H) 10.99 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(Cl)Cl>[C:21]1([C:27]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
27 g of triethylamine are added to a solution of 90 g of ethyl 2-aminothiazol-4-ylglyoxylate in 225 ml of dimethylformamide and 375 ml of CH2Cl2 at -15° and 75 g of triphenylchloromethane are then added at -30°. After 15 minutes at -30°, the mixture is stirred for 3 hours without a cooling bath and 500 ml of CH2Cl2 are added to the resulting reaction mixture, the mixture is washed with 300 ml of 1 N HCl and then twice with 200 ml of water, the organic phase is dried over Na2SO4 and the solvent is evaporated off.
Reaction SMILES: CC1N=C(C2C=CC([CH:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[N:21]=4)[CH2:15][CH2:14]3)=CC=2)ON=1.Cl.[O:35]1[CH:39]=[N:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](C3COCCNC3)=[CH:42][CH:41]=2)=[N:36]1>>[CH3:26][N:25]1[C:24](=[O:27])[CH:23]=[C:22]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)[N:21]=[C:20]1[N:16]1[CH2:15][CH:14]([C:43]2[CH:42]=[CH:41][C:40]([C:37]3[N:38]=[CH:39][O:35][N:36]=3)=[CH:45][CH:44]=2)[CH2:13][O:19][CH2:18][CH2:17]1
Reactant: Cc1noc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)n1
Reactant: c1nc(-c2ccc(C3CNCCOC3)cc2)no1
Agent: Cl
Product: Cn1c(N2CCOCC(c3ccc(-c4ncon4)cc3)C2)nc(-c2ccncn2)cc1=O

Procedure:
1-Methyl-2-[6-(4-[1,2,4]oxadiazol-3-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one was prepared the same procedure as that of 2-{7-[4-(3-methyl-[1,2,4]-oxadiazole-5-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one except for utilizing 6-(4-[1,2,4]oxadiazol-3-yl-phenyl)-[1,4]oxazepane hydrochloride instead of 7-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-[1,4]oxazepane hydrochloride. 1-Methyl-2-[6-(4-[1,2,4]oxadiazol-3-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (A086) was obtained as white solid (0.05 g, 0.12 mmol, 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C@H:11]1[CH2:16][NH:15][CH2:14][C@@H:13]([CH3:17])[N:12]1[CH2:18][CH2:19][CH3:20].Cl>>[Cl:9][C:4]1[CH:3]=[C:2]([N:15]2[CH2:14][C@@H:13]([CH3:17])[N:12]([CH2:18][CH2:19][CH3:20])[C@@H:11]([CH3:10])[CH2:16]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CCCN1[C@H](C)CNC[C@@H]1C
Agent: Cl
Product: CCCN1[C@H](C)CN(c2ccc(Cl)c(Cl)c2)C[C@@H]1C

Procedure:
Beginning with 4-bromo-1,2-dichlorobenzene and cis-2,6-dimethyl-1-propyl-piperazine, the title compound was recovered by the procedure described in Preparation 9: m.p. 225° C. (HCl), MS m/z (rel. intensity, 70 eV)) 301 (M+, 24), 271 (64), 112 (bp), 70 (47), 56 (53).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.CS([Cl:34])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:34][C@@H:6]1[CH2:7][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:14][CH:15]=2)[CH2:5]1
Reactant: OC[C@H]1CCCN1CCc1ccc(N2CCCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cl[C@@H]1CCCN(CCc2ccc(N3CCCC3)cc2)C1
Reaction time: 2 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-pyrrolidinophenethyl)pyrrolidine (4.96 g, 19.1 mmol) was dissolved in 70 ml of dichloromethane. 3.21 g (24.8 mmol) of diisopropylethylamine and 2.84 g (24.8 mmol) of methanesulfonyl chloride were added to the obtained solution under stirring under cooling with ice. They were stirred under cooling with ice for 1 hour and then at room temperature for 2 hours. The reaction mixture was distributed into dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-pyrrolidinophenethyl)piperidine in the form of a light yellow solid (3.23 g, 61%).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(NCc3ccccc3)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
145.0 g (407.9 mmol) of tert-butyl 1-[3-(benzylamino)-4-fluorobenzyl]cyclopropanecarboxylate were dissolved in 1450 ml of ethanol, and 9.67 g of palladium hydroxide (20% on carbon) were added. The suspension was stirred at RT under a hydrogen atmosphere at standard pressure for 18 h. The reaction mixture was then filtered off with suction through kieselguhr, and the filtrate was concentrated. After drying under high vacuum, 500 ml of pentane were added to the residue, resulting in the precipitation of the product. The suspension was stirred in an ice bath for 1 h. The solid was then filtered off with suction, washed twice with pentane and dried under high vacuum. 88.5 g (73.6% of theory) of the title compound were thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24](C(Cl)=O)=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:38](=O)([O-])[OH:39].[Na+]>C(N(CC)CC)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:38]([C:35]2[CH:34]=[CH:33][C:32]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:37][CH:36]=2)=[O:39])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(-c5ccccc5)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 25 h
Yield: 10 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was suspended in triethylamine/methylene chloride (3 ml/2 ml), commercially available biphenylcarbonyl chloride (80 mg) was added, and the admixture was stirred at room temperature for 25 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture, and the resulting admixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone and further by washing resulting crystals with acetoneto obtain 9 mg of the title compound (yield: 10%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])[CH:38]=[CH:39][CH:40]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42](=[O:43])[NH:44][CH:45]3[CH2:47][CH2:46]3)[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(Cc1cccc(Br)c1)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1)NC1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 2-(3-bromo-phenyl)-N-cyclopropyl-acetamide (42.0 mg, 0.17 mmol), and Pd[P(Ph)3]4 (14.3 mg, 7.5 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.3 mg. MS: 498.2 (M+H+); H1 -NMR (DMSO-d6): δ (ppm) 0.31-0.39 (m, 2H), 0.52-0.60 (m, 2H), 1.74-2.00 (m, 3H), 2.10-2.30 (m, 1H), 2.50-2.62 (m, 1H), 3.34-3.54 (m, 2H), 4.28-4.38 (m, 1H), 4.85-5.08 (m, 2H), 6.95-7.55 (m, 12H), 7.80-7.92 (m, 1H), 8.05-8.18 (m, 1H), 10.05-10.12 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:5][C:6]=1[C:7](=[O:10])[CH2:8][CH3:9].O1CCCC1.[BH4-].[Li+]>Cl>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[O:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9]
Reactant: CCC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-one (0.68 g, 2.4 mmol) and tetrahydrofuran (5 mL) are stirred at 0° C. Lithium borohydride (0.14 g, 6.36 mmol) is added and the mixture is stirred 10 min at 0° C., and 30 min at room temperature. The mixture is diluted with 1M aqueous hydrochloric acid and washed with ethyl acetate (three 50 mL portions). The organic washes are dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified over silica eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes ethyl acetate to afford 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol as an ivory solid, 0.69 g, 100%. MS (M++1)286.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[S:22][CH:21]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:29][C:25]1[CH:24]=[C:23]([C:20]2[C:18]3[N:19]=[C:14]([NH:13][C:10]4[CH:11]=[N:12][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][CH:9]=4)[N:15]=[CH:16][C:17]=3[S:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
N-(6-Morpholinopyridin-3-yl)-7-(3-nitro phenyl)thieno[3,2-d]pyrimidin-2-amine (476 mg, 1.10 mmol) was dissolved in ethanol (3.5 mL) and tin(II) chloride dihydrate (1238 mg, 5.48 mmol) was added. The reaction mixture was stirred at 80° C. for 2 hours. After removing ethanol by distillation under reduced pressure, ammonia water was slowly added to make pH 5. Sodium carbonate was added to thus prepared yellow precipitate until the pH reached 7. The precipitate was filtered and washed several times with ethyl acetate. The filtrate was concentrated and the resultant target compound (338 mg, 76%) was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH2:25]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH:25][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: NCc1ccccc1Cl
Reactant: COc1cc(-c2cn[nH]c2)ccc1C(=O)O
Product: COc1cc(-c2cn[nH]c2)ccc1C(=O)NCc1ccccc1Cl

Procedure:
Example 53 was synthesized by following a similar procedure as described in Example 1 by replacing Intermediate 1 with Intermediate 2 and replacing (3-methoxyphenyl)methanamine with (2-chlorophenyl)methanamine. LCMS (ESI) m/z: 342.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (1H, s), 8.13 (2H, s), 7.73 (1H, d, J=8.03 Hz), 7.39 (1H, dd, J=7.65, 1.63 Hz), 7.16-7.34 (5H, m), 4.50 (2H, d, J=6.02 Hz), 3.93 (3H, s). Analytical HPLC RT=7.97 min (Method A), 7.21 min (Method B).