Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:24]1[CH2:25][C:29]2[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]1)=[O:6]
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1Cl
Reactant: CCN(CC)Cc1ccccc1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1Cl)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 134.5 %

Procedure:
A stirred mixture of 2-chloro-4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D28) (0.10 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.8 g) in DCM (10 ml) at rt was treated with isoindoline (0.031 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E61) as a white solid (0.083 g). MS electrospray (+ion) 399/401 (MH+). 1H NMR δ (DMSO-d6): 9.90 (1H, s), 7.41 (2H, m), 7.28 (3H, m), 7.11 (1H, s), 7.02 (1H, m), 4.83 (2H, s), 4.50 (2H, s), 4.14 (2H, t, J=5.9 Hz), 3.45 (2H, m), 3.25 (2H, m), 2.90 (2H, m), 2.18 (2H, m), 1.87-1.30 (6H, m).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:43]=[CH:42][C:9]([O:10][C:11]3[C:12]([CH:34]4[CH2:38][CH2:37][CH2:36][N:35]4[C:39](=[O:41])[CH3:40])=[CH:13][C:14]4[N:18](COCC[Si](C)(C)C)[C:17]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)=[N:16][C:15]=4[CH:33]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>FC(F)(F)C(O)=O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[C:12]([CH:34]4[CH2:38][CH2:37][CH2:36][N:35]4[C:39](=[O:41])[CH3:40])=[CH:13][C:14]4[NH:18][C:17]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)=[N:16][C:15]=4[CH:33]=3)=[CH:42][CH:43]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(-c3cnco3)cc1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24 mg of 1-(2-(6-(4-oxazol-5-yl-phenoxy)-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone was dissolved in 1 ml of trifluoroacetic acid, and the reaction liquid was stirred at room temperature for 2 hours. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][SH:28]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][S:28][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)CCS
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCC2)CC1
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCC2)C2CCC(C)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea (Example 202) and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si:6]1(C2C=CC=CC=2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[F:32]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][Si@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COCCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc([Mg]Br)cc1F
Product: COCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 34.5 g of 4-(4-(3-methoxypropyl)-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.C(OC([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=O)(C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH-].[Na+].Cl>C(OCC)(=O)C.C(O)C.ClCCl>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43]([N:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)=[O:45])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-{6-[2-(2-Ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid (150 mg), piperazine-1-carboxylic acid tert-butyl ester (54 mg), PyBroP (130 mg), diisopropylethylamine (85 □l) and dichloromethane (3 mL) were combined together and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate and concentrated to dryness. The total amount of the product obtained from the previous step was dissolved in ethanol (2 mL) and 10 M NaOH solution was added (3 eq.). The resulting reaction mixture was stirred at room temperature for 5 h. Then it was neutralized with 3 N HCl and extracted into ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, concentrated to dryness, redissolved in a mixture of TFA and dichloromethane (1:1, 2 mL) and stirred at room temperature for 3 h. The solvents were removed under reduced pressure and the title compound was purified on reverse-phase HPLC.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]([OH:12])=O)=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1CCOCC1.CN.CCN=C=NCCCN(C)C.Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C=O)C.C1COCC1>[CH3:16][NH:17][C:10]([C:8]1[NH:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14])=[O:12]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1[nH]c(C(C)(C)C)cc1[N+](=O)[O-]
Yield: 65.4 %

Procedure:
To a solution of 5-tert-butyl-3-nitropyrrole-2-carboxylic acid (2.01 g, 9.5 mmol) in a solution of anh. THF and anh. DMF (3:1, 100 mL) at 0° C. was added N-methylmorpholine (2.1 mL, 19 mmol, 2.0 equiv), followed by methylamine (2M in THF, 5.93 mL, 11.1 mmol, 1.25 equiv) and EDCI.HCl (2.85 g, 14.9 mmol, 1.57 equiv). The resulting mixture was allowed to warm to room temp. and stirred at that temp. overnight. The reaction mixture was diluted with H2O (100 mL), then made acidic with a 10% citric acid solution, and extracted with EtOAc (2×50 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (15% CH2Cl2/hex) to give 2-(N-methylcarbamoyl)-5-tert-butyl-3-nitropyrrole (1.40 g, 66%) as a yellow solid: 1H NMR (DMSO-d6) δ1.29 (s, 9H), 2.76 (d, J=4.4 Hz, 3H), 6.36 (d, 2.9 Hz, 1H), 8.59-8.60 (m, 1H), 12.19 (br s, 1H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([N:13]([CH3:36])[CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)=O)=[C:21](F)[CH:20]=1)[CH:11]=[CH2:12]>CC(N(C)C)=O>[CH2:10]([N:13]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)=[N:3][N:2]2[CH3:1])=[CH:23][C:24]=1[F:25])[CH3:36])[CH:11]=[CH2:12]
Reactant: CNN
Reactant: C=CCN(C)C/C=C/COc1cc(F)c(C(=O)c2ccc(Br)cc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/COc1cc2c(cc1F)c(-c1ccc(Br)cc1)nn2C

Procedure:
A mixture of 0.53 ml of methyl hydrazine and 0.17 g of potassium carbonate is stirred in 5 ml of DMA at room temperature. After the addition of 0.44 g of (E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2,5-difluoro-phenyl]-(4-bromo-phenyl)-methanone in 5 ml of DMA the mixture is boiled at 120° C. After filtration the filtrate is concentrated at 80° C./0.3 Torr, taken up in methylene chloride, filtered over sodium sulphate and concentrated. The residue consisting of the title compound is dissolved in ether/hexane, treated with 0.11 g of fumaric acid and stirred. After filtration and drying there is obtained 0.41 g of (E)-allyl-[4-[3-(4-bromo-phenyl)-5-fluoro-1-methyl-1H-indazol-6-yloxy]-but-2-enyl]-methyl-amine.fumarate, m.p. 135°-137° C.
Reaction SMILES: ClC1([C:8]2[CH:18]=[CH:17][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][NH:16][C:10]=3[CH:9]=2)C=CC=NN1.NN>C(O)C.[Pd]>[NH:16]1[C:10]2[CH:9]=[CH:8][CH:18]=[CH:17][C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]1
Reactant: ClC1(c2ccc3c(c2)NC=CC=C3)C=CC=NN1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: C1=CNc2ccccc2C=C1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a solution of the 8-(3-chloropyridazin-3-yl)benzazepine (0.77 g, 2.0 mmol) from step L above in ethanol (50 mL) were added hydrazine (1.0 mL, 20 mmol) and palladium on carbon (0.11 g). The reaction solution was heated under reflux for 16 h, and then it was cooled to room temperature, filtered through a plug of Celite and concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane to 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to give the racemic benzazepine (0.20 g, 28%) as a yellow foam: 1H NMR (CDCl3, 500 MHz) δ 9.15 (dd, J=4.5, 1.5 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.5, 1.5 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.5, 5.0 Hz, 1H), 6.92-6.80 (br, 1H), 6.77-6.70 (br, 3H), 4.38 (d, J=8.5 Hz, 1H), 3.98 (d, J=13.0 Hz, 1H), 3.85 (d, J=14.0 Hz, 1H), 3.14-3.08 (m, 1H), 3.01-2.96 (m, 1H), 2.38 (s, 3H), 2.87-2.14 (m, 2H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](S)=[N:11][C:10]=2[CH:15]=1)(=[O:5])=[O:4])[CH3:2].S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:15][C:10]=2[N:11]=1
Reactant: CCS(=O)(=O)c1ccc2oc(S)nc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc2oc(Cl)nc2c1
Reaction time: 0.75 h

Procedure:
8 mmol of 5-Ethanesulfonyl-benzooxazole-2-thiol were dissolved in 10 ml of thionyl chloride. 1 drop of N,N-dimethylformamide is added and the reaction mixture hold at 65° for 45 min. Evaporation of the solvent yields the title compound as brownish solid.
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.Cl.[CH3:37][O:38][C:39]1[CH:48]=[CH:47][C:42]([C@@H:43]([NH2:46])[CH2:44][OH:45])=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.[Cl-].[Na+].O.O.C(N(CC)CC)C>[C:14]([NH:13][C@@H:12]([C:11]([NH:46][C@H:43]([C:42]1[CH:47]=[CH:48][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)[CH2:44][OH:45])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc([C@@H](N)CO)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Yield: 112.2 %

Procedure:
Prepared according to the method described in Example 11(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (3.11 g; 6.38 mmol; see Example 4(a) above), (R)-4-methoxy-α-hydroxymethylbenzylamine hydrochloride (1.43 g; 7.02 mmol) and triethylamine (0.97 g; 9.57 mmol; instead of DiPEA) in CH2Cl2 (100 mL), 18 hours reaction time. The reaction mixture was submitted to aqueous work up using water, 1N HCl and brine, then dried, filtered and concentrated to give a yellow solid (3.69 g) which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([CH3:23])[CH:3]=1.[Cl:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>C1COCC1>[Cl:24][CH2:25][CH2:26][NH:27][C:28]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([CH3:23])[CH:3]=1)=[O:29]
Reactant: O=C=NCCCl
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)NCCCl)cc2C)n1

Procedure:
To a slurry of 4-(2-(4-amino-2-methylphenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.500 g, 1.63 mmol) in THF (3.3 mL) under nitrogen was added 1-chloro-2-isocyanatoethane (0.157 mL, 1.79 mmol). The reaction became clear and brown, and then a precipitate formed. Additional THF (4 mL) was added to promote stirring, and the reaction was allowed to stir for 16 h. The mixture was filtered, the solid was rinsed with diethyl ether, and dried in vacuo to give 1-(2-chloroethyl)-3-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)urea as a tan solid. MS m/z=413 [M+1]+. Calc'd for C20H21ClN6O2: 412.14.
Reaction SMILES: [CH2:1]([C:5]1([CH3:32])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:31])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].CC(O)C.C(=O)=O.[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1([CH3:32])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([OH:31])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C=CCCC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Reaction time: 3 h
Yield: 115 %

Procedure:
A solution of ethyl 5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(2-methoxy-2-oxoacetyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (0.44 g, 1.00 mmol, 1 equiv) and R-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborlidine (1.59 mL of a 1 M solution in toluene, 1.59 mmol, 1.6 equiv) in toluene (10 mL) was cooled to −30° C. (IPA/dry ice). Catecholborane (0.34 mL, 1.59 mmol, 1.6 equiv) was added and the reaction was stirred at −15° C.-30° C. for 3 h. The reaction was then added to 10% K2CO3 and extracted with ether (×3). The combined ether extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (30-100% EtOAc/hex) to provide the product (0.51 g, ˜100%) as a viscous colorless oil. NMR shows contamination with a CBS byproduct accounting for extra mass. 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.40 (s, 1H), 5.98-5.84 (m, 1H), 5.61 (d, J=11.0 Hz, 1H), 5.17-4.98 (m, 2H), 4.55-4.46 (m, 2H), 3.81 (s, 3H), 3.61 (t, J=10.9 Hz, 2H), 3.11-2.94 (m, 4H), 2.44 (d, J=0.9 Hz, 3H), 2.18-2.09 (m, 2H), 1.82-1.53 (m, 4H), 1.50-1.44 (m, 3H), 1.16 (s, 3H); LCMS (ESI, M+1): 444.25.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:22]=[C:23]([C:31]([S:34]([CH3:37])(=[O:36])=[O:35])([CH3:33])[CH3:32])[CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH:16]=2)=[CH:11][CH:10]=1)=[O:5])C.[Li+].[OH-]>C1COCC1>[CH3:37][S:34]([C:31]([C:23]1[CH:24]=[C:25]2[C:30](=[C:21]([C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([CH:7]5[CH2:8][CH:6]5[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=4)[CH:20]=[CH:19][CH:18]=3)[CH:22]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)([CH3:33])[CH3:32])(=[O:36])=[O:35]
Reactant: CCOC(=O)C1CC1c1ccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(-c3ccc(C4CC4C(=O)O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-{3′[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl 4-yl}-cyclopropanecarboxylic acid ethyl ester (1.0 eq.) from Step 1, in THF:MEOH (2:1; 0.2M) was added aqueous LiOH (2M; 0.2.0 eq.). The mixture was stirred for 12 h at rt, quenched with HCl 10% and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Crystallization in Hex:EtOAc afforded the title compound as a white solid. 1H NMR (400 MD, acetone-d6): δ 8.96 (dd, 1H), 8.50 (dd, 1H), 8.32 (d, 1H), 8.24 (d, 1H), 8.03 (t, 1H), 7.73–7.68 (m, 4H), 7.63–7.59 (m, 2H), 7.32 (d, 2H), 2.75 (s, 3H), 2.53 (m, 1H), 2.03 (s, 6H), 1.97 (m, 1H), 1.56 (m, 1H), 1.46 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:28][CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccncc1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccncc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-pyridin-4-yl-methylamine (CA [58088-57-6]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:16])[C:13]([OH:15])=O)[CH2:7][CH2:6][CH2:5]2.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:16])[C:13]([N:26]1[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]1)=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C[C@H](C(=O)O)N1CCCc2cc(F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C(=O)N1CCN(c2ccccc2)CC1)N1CCCc2cc(F)ccc21
Temperature: 0 °C
Yield: 67.5 %

Procedure:
The (R)-2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)propanoic acid (7.9 mmol), 1-phenyl piperazine (1.2 mL, 7.9 mmol), HATU (3.0 g, 7.9 mmol), NaHCO3 (660 mg, 7.9 mmol) and CH2Cl2 (10 mL): DMF (10 ml) were stirred at rt for 19 h. The solution was poured into an ice-water mixture (100 ml), followed by an extraction with CH2Cl2 (3×75 mL). The organic layer was dried over MgSO4 and evaporated in vacuo. After evaporating the solvents under reduced pressure, the residue was purified by silica gel chromatography using 20-50% ethyl acetate in hexane gave (R)-2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperazin-1-yl)propan-1-one (1.96 g) as white solid. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=369.47; tR=3.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:5]=[CH:4][N:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:23][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: NC1CCCC1
Reactant: O=C(Nc1ccnc(Cl)c1)Oc1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1ccnc(Cl)c1)NC1CCCC1
Yield: 85.8 %

Procedure:
A stirred solution of 3.5 grams (0.0141 mole) of phenyl N-(2-chloro-4-pyridinyl)carbamate and 1.7 ml (0.0172 mole) of cyclopentylamine in 60 ml of acetone was heated under reflux for three hours. The reaction mixture was cooled and concentrated under reduced pressure to a residual oil. The oil was dissolved in 20 ml of methylene chloride and passed through a column of silica gel. Elution was accomplished with 5% and 10% acetone-methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 2.9 grams of N-(2-chloro-4-pyridinyl)-N'-cyclopentylurea; m.p. 119°-121° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([C:7]2[N:8]([CH2:19][CH3:20])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([NH2:16])=[CH:11][CH:10]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCn1c(C2CCCCC2)cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(C2CCCCC2)cc2cc(N)ccc21
Reaction time: 4 h
Yield: 91.7 %

Procedure:
To a suspension of 10% Pd/C (380 mg, 0.36 mmol) in 95° ethanol (50 ml) a solution of 2-cyclohexyl-1-ethyl-5-nitro-1H-indole (4.8 g; 18 mmol) in 95° ethanol (100 ml) was added and the mixture underwent hydrogenation in a Parr hydrogenator (H2, 30 psi) for 4 hours. The residue was filtered under vacuum through Celite to remove the catalyst and the solvent evaporated to give crude 2-cyclohexyl-1-ethyl-1H-indol-5-amine (4 g) which was used without any further purification.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[CH2:13]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([CH:2]([CH3:12])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)=[O:4])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N1CCC(Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
A solution of 26.48 g (0.107 mol) of 2-bromo-3'-chloropropiophenone in 70 ml of acetonitrile is placed in a 500 ml three-necked round-bottomed flask equipped with a pressure equalizing funnel, a calcium chloride drying tube and a magnetic stirrer, and 37.5 g (0.214 mol) of 4-benzylpiperidine are then added at ambient temperature over a period of about 20 minutes, without stirring. The mixture warms up; it is allowed to return to ambient temperature and, after 3 hours, 4-benzylpiperidine hydrobromide is crystallised by cooling the mixture on ice and triturating it. The crystals are filtered off and washed with acetonitrile (2×10 ml) and the filtrate is diluted with 200 ml of diethyl ether. Further 4-benzylpiperidine hydrobromide precipitates and is filtered off. 100 ml of 3N hydrochloric acid are added to the filtrate and the mixture is stirred. Three phases form. The two lower phases are collected, the upper phase is taken up in a few ml of water and the aqueous phase obtained is combined with the two phases previously separated off. Precipitation occurs. The mixture is cooled on ice, stirred and filtered on a glass frit and the first crop of precipitate is dried in a vacuum oven. The filtrate deposits a second precipitate, which is shown by thin layer chromatography to be the same product as the first crop. A total of 34.06 g of crystals of the hydrochloride, melting at between 189° and 198° C., is thus recovered, which is used as such in the subsequent reduction.