Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[N:7]([CH3:17])[C:6](=[O:18])[C:5]2[CH:19]=[CH:20][CH:21]=[N:22][C:4]1=2)[CH3:2].O.O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(O)(=O)C.Cl>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]([CH3:17])[C:6](=[O:18])[C:5]3[CH:19]=[CH:20][CH:21]=[N:22][C:4]=3[N:3]([CH2:1][CH3:2])[C:9]=2[CH:10]=1
Reactant: CCN1c2cc([N+](=O)[O-])ccc2N(C)C(=O)c2cccnc21
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(N)ccc2N(C)C(=O)c2cccnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.7 %

Procedure:
To a solution of 0.3 g (1 mmol) of 6,11-dihydro-11-ethyl-6-methyl-9-nitro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one in acetic acid (5 ml) was added a solution of SnCl2.2H2O (1.7 g) in concentrated hydrochloric acid (2.2 ml). The mixture was stirred at room temperature for 6 hours, and then poured into a saturated sodium bicarbonate solution and made basic with aqueous sodium hydroxide. The aqueous phase was then extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo. The solid material obtained was recrystallized from ethyl acetate to give 0.12 g (44% of theory) of 6,11-dihydro-9-amino-11-ethyl-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 193°-195° C.
Reaction SMILES: [Cl:1][C:2]([Cl:54])([Cl:53])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:52])[C@@H:14]([NH:21][C:22](=[O:51])[C@@H:23]([NH:27][C:28](=[O:50])[C:29]([CH3:49])([CH3:48])/[CH:30]=[CH:31]/[C:32]2[CH:41]=[C:40]3[C:35]([CH:36]=[CH:37][C:38]([C@H:42]([O:44][C:45](=[O:47])[CH3:46])[CH3:43])=[N:39]3)=[CH:34][CH:33]=2)[CH:24]([CH3:26])[CH3:25])[CH2:15]N2C=CC=N2)[NH:8]1)=[O:6].ClC(Cl)(Cl)[CH2:57][O:58]C([C@@H]1CCCN(C(=O)[C@@H](NC(=O)[C@@H](NC(OC(C)(C)C)=O)C(C)C)COC)N1)=O>>[Cl:1][C:2]([Cl:54])([Cl:53])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:52])[C@@H:14]([NH:21][C:22](=[O:51])[C@@H:23]([NH:27][C:28](=[O:50])[C:29]([CH3:49])([CH3:48])/[CH:30]=[CH:31]/[C:32]2[CH:41]=[C:40]3[C:35]([CH:36]=[CH:37][C:38]([C@H:42]([O:44][C:45](=[O:47])[CH3:46])[CH3:43])=[N:39]3)=[CH:34][CH:33]=2)[CH:24]([CH3:26])[CH3:25])[CH2:15][O:58][CH3:57])[NH:8]1)=[O:6]
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C)C(=O)N[C@H](C(=O)N[C@@H](Cn3cccn3)C(=O)N3CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N3)C(C)C)cc2n1
Reactant: COC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Product: COC[C@H](NC(=O)[C@@H](NC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)OC(C)=O)nc2c1)C(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1

Procedure:
Compound 117c was prepared in the same manner as (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester using (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-methoxy-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (700 mg, 1.25 mmol) instead of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester to afford the title compound as an off white foam (460 mg, 48%) and as a 1:1 mixture of two diastereoisomers. LCMS (m/z) 770.2 [M+H], Tr=3.06 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.[Cl:20][C:21]([F:26])([F:25])[C:22](O)=[O:23]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:20][C:21]([F:26])([F:25])[C:22]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:23]
Reactant: O=C(O)C(F)(F)Cl
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)Cl
Reaction time: 8 h
Yield: 23.9 %

Procedure:
200 mg (2.13 mmol) of 2-aminopyridine was dissolved in 5 ml of dichloromethane, 491 mg (2.55 mmol) of EDC-HCl, 311 mg (2.55 mmol) of DMAP and 187 μl (2.23 mmol, 290 mg) of chlorodifluoroacetic acid were added thereto in sequence, and the resulting mixture was stirred overnight. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed with water and 1% hydrochloric acid, and then dried over anhydrous magnesium sulfate to obtain 105 mg (yield 24%) of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:22]([OH:27])[OH:23])=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1
Reactant: COc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cnc(F)c(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round-bottomed flask, diisopropylamine (Aldrich, 1.40 mL, 9.99 mmol) was dissolved into THF (6 mL). nBuLi (Aldrich, 2.5 M in hexanes, 3.60 mL, 8.99 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min then cooled to −78° C. 2-fluoro-5-methoxypyridine (0.520 g, 4.09 mmol) in 4 mL of THF was added slowly, and the mixture was stirred at that temperature for 40 min. Triisopropyl borate (Aldrich, 2.07 mL, 8.99 mmol) in a total of 4 mL of THF was added slowly and the mixture was stirred at −78° C. for 5 min. The cold bath was removed and the reaction mixture was stirred at room temperature for 1 h. 1 N NaOH (20 mL) was added to the mixture to quench the reaction. The layers were separated and the aqueous phase was treated with 5 N HCl to adjust the pH to around 5. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford 0.593 g of tan color solid. This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[C:43]4[C:38](=[CH:39][C:40]([Cl:44])=[CH:41][CH:42]=4)[N:37]=[CH:36][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccnc4cc(Cl)ccc34)ccc2n1-c1ccc(OC(F)(F)F)cc1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (100 mg, 0.22 mmol; see step (b) Example 9), 4,7-dichloroquinoline (66 mg, 0.33 mmol), K2CO3 (60 mg, 0.43 mmol) and DMF (2 mL) was stirred at 100-110° C. for 3 h, cooled, diluted with H2O (20 mL) and extracted with Et2O (30 mL). The extract was washed with H2O, dried (Na2SO4, concentrated and purified by chromatography to give the title compound. Yield 48 mg (36%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16]2[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][C:28]2=[O:29])([CH3:14])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(Nc2ccccc2N)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Product: CC1(n2c(=O)[nH]c3ccccc32)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
A mixture of 121 mg N-(1-benzyl-4-methyl-piperidin-4-yl)-benzene-1,2-diamine and 79 mg CDI in 5 mL dichlormethane was stirred 24 h at RT. Water was added and the mixture was extracted with ethylacetate. The organic layer was concentrated to give 119 mg of the desired product. (M+H)+:322
Reaction SMILES: [O:1]1[CH:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH:4]2[O:3][CH2:2]1.[ClH:16]>ClCCl.C(O)(C)C>[ClH:16].[O:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2OCOC2C1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: C1OC2CNCC2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (19.77 g) was dissolved in dichloromethane (500 mL) and cooled in an ice bath. Cold (from the fridge) HCl in isopropanol (150 mL; 5N) solution was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated off and the residue triturated under ether. The precipitate was collected by filtration, washed with ether and dried to give tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride (13.18 g; 95%) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH:14][C:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1

Procedure:
22.4 Using general procedure C (3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was reacted with 5-chlorothiophene-2-carboxylic acid to give (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Off-white solid. MS 347.3 ([M+H]+)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/C)=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3].Br[C:18]1C=CC(S(C)(=O)=O)=CC=1[N+]([O-])=O.C(B1OC(C)(C)C(C)(C)O1)(C)=C>>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])([CH3:12])=[CH2:18]
Reactant: C/C=C/c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: C=C(C)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]

Procedure:
Following the general method as outlined in Intermediate 59, starting from 2-bromo-5-methylsulfonylnitrobenzene and isopropenylboronic acid pinacol ester, the title compound was obtained as a brown oil in quantitative yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-N-(4-fluorobenzyl)glycinate (12.37 g, 41.63 mmol) in MeOH (180 mL) was added 5 N aqueous NaOH solution (18.32 mL, 91.58 mmol). The reaction was stirred under inert atmosphere at ambient temperature for 2 h. The solvent was removed in vacuo, and the remaining residue was taken up in water and washed twice with CHCl3. The aqueous layer was cooled to 0° C., acidified to pH 2 with 1 N aqueous HCl solution, and saturated with NaCl. The mixture was extracted with EtOAc three times, and the organic layers were dried (MgSO4) and concentrated in vacuo to afford the acid as a light yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:44])[C@@H:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:35]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:44])=[O:33])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Product: O=C(O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and (R)-(+)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 90-92° C.; MS m/e 679 (M−H+;
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(OC([N:22]1[CH2:26][C@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH:23]1[C:33](O)=[O:34])=O)(C)(C)C>>[C:27]1([C@H:25]2[CH2:26][NH:22][CH:23]([C:33]([NH:1][C:2]3[CH:11]=[CH:10][C:9]([C:12]([NH2:14])=[O:13])=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)=[O:34])[CH2:24]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)CC1C(=O)O
Reactant: NC(=O)c1ccc(N)c2cccnc12
Product: NC(=O)c1ccc(NC(=O)C2C[C@@H](c3ccccc3)CN2)c2cccnc12

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 27 by using 5-aminoquinoline-8-carboxamide coupled with (4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid, followed by removal of the protecting group to afford Example 28. LC-MS. (M+H=361, obsd=361).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22]([S:25]([N:28]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]1=2)CO.I([O-])(=O)(=O)=O.[Na+].CO.[BH4-].[Na+]>C1COCC1.O>[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:8]=[CH:7][C:6]=1[N:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22]([S:25]([N:28]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]1=2)=[O:1]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2C(O)CO)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-(2-(1,2-dihydroxyethyl)-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (from EXAMPLE 204, intermediate in Step 2; 0.100 g, 0.161 mmol) in THF (0.619 ml)/water (0.619 ml) was added sodium periodate (0.052 g, 0.241 mmol). The reaction mixture was stirred at RT for 2 h. Upon completion, the reaction was filtered and washed well with THF. The filtrate was concentrated in vacuo and 4-(2-formyl-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was carried on without purification. To a solution of 4-(2-formyl-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.095 g, 0.161 mmol, 100% yield) in methanol (1.609 ml, 0.161 mmol) was added sodium borohydride (0.012 g, 0.322 mmol) at 0° C. (turned from yellow to clear solution upon addition), and the reaction was stirred in the ice-bath for 30 minutes until completion. The reaction was quenched with sat ammonium chloride solution (aq) and washed with DCM (×2). After drying via phase separator (Radley's Discovery Technology), the organics were concentrated in vacuo to yield an orange oil. The oil was taken up in DCM, and TFA was added (color change from orange solution to light pink). The reaction was stirred for 1 h until complete deprotection. The material was concentrated in vacuo and purified via silica gel chromatography, eluting with 0-100% ethyl acetate in heptane to yield 4-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.017 g, 0.036 mmol, 22.41% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.58 (br. s., 1 H) 3.66-3.79 (m, 1 H) 4.30-4.37 (m, 2 H) 4.38-4.58 (m, 2 H) 5.42 (t, J=5.48 Hz, 1H) 6.12 (d, J=8.51 Hz, 1 H) 6.78 (d, J=4.50 Hz, 1 H) 7.10 (dd, J=8.46, 2.10 Hz, 1H) 7.15 (d, J=2.05 Hz, 1 H) 7.21 (d, J=4.60 Hz, 1 H) 7.53 (d, J=8.31 Hz, 1 H) 7.73 (d, J=8.22 Hz, 1 H) 7.92 (s, 1 H) 12.55 (br. s., 1 H). m/z (ESI) 472.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][C:8](N2CCCC2)=[C:7]([C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:18](C)C)[CH2:6]1)=[O:4].C([O-])(=O)C.[NH4+]>C(O)C>[OH:26][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:18]=[C:8]2[CH2:9][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]=12
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C1=C(N2CCCC2)CN(C(=O)OC)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c1O)CN(C(=O)OC)C2

Procedure:
A solution of 10.96 g of N-methoxycarbonyl-3-(2-ethoxycarbonyl-3-dimethylaminoacryloyl)-4-pyrrolidino-2,5-dihydropyrrole and 20 g of ammonium acetate in 250 ml of dry ethanol is refluxed for 90 minutes. The solution is cooled in an ice bath and the precipitate is filtered off to yield ethyl 4-hydroxy-5,7-dihydro-6-methoxycarbonylpyrrolo[3,4-b]pyridine-3-carboxylate, mp 274°-276° (dec); NMR (CF3COOD): 11.08 (s), 9.14 (s), 5.20 (s), 5.00 (s), 4.65 (q), 3.99 (s) and 1.52 (t).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]([CH2:17][CH2:18][CH3:19])[CH2:12][N:13]([CH3:16])[CH2:14][CH:15]=2)=[CH:6][CH:5]=1.B(F)(F)F.CC[O:26]CC.[OH-].[K+].OO>COCCOC.O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:11]([CH2:17][CH2:18][CH3:19])[CH2:12][N:13]([CH3:16])[CH2:14][CH:15]2[OH:26])=[CH:6][CH:5]=1
Reactant: CCCC1CN(C)CC=C1c1ccc(Cl)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCCC1CN(C)CC(O)C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
2.23 g (60 mmol) of sodium borohydride were added spatula-wise to a suspension of 9.7 g (39 mmol) of (RS)-4-(4-chloro-phenyl)-1-methyl-3-propyl-1,2,3,6-tetrahydro-pyridine in 80 ml of 1,2-dimethoxyethane in such a manner that the temperature did not rise above 35° C. Subsequently, 13.2 ml of boron trifluoride etherate dissolved in 15 ml of 1,2-dimethoxyethane were added dropwise during 45 minutes and thereafter the reaction mixture was stirred at room temperature for 2 hours. Subsequently, firstly a solution of 15.65 g (277 mmol) of potassium hydroxide dissolved in 60 ml of water was slowly added dropwise at about 30° C. and thereafter within 15 minutes 11.2 ml of a 30% hydrogen peroxide solution was added, with the temperature rising to 40° C. Subsequently, the mixture was boiled under reflux for 2.5 hours. For the working-up, the cooled reaction mixture was filtered over Dicalit and this was rinsed with ethyl acetate. The solution obtained was treated with 100 ml of ethyl acetate and 100 ml of water, the organic phase was separated and then the aqueous phase was back-extracted with 100 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 8.64 g (73% of theory) of (3RS,4SR, 5RS)-4-(4-chloro-phenyl)-1-methyl-5-propyl-piperidin-3-ol as a colourless solid; MS: 267 (M)+.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[N+:22]([O-])([O:24]CCCCC)=[O:23]>>[CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15]
Reactant: CCCCCO[N+](=O)[O-]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc([N+](=O)[O-])cc1)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Amyl nitrate (40 ml.) is added in 10 ml. increments at two hour intervals to 2-methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.36 g., 0.03 mole) in polyphosphoric acid (150 g.) at 50°-60° C. with stirring. The total heating period is 8 hours. The reaction mixture is treated with crushed ice-water to precipitate 4.82 g. of 2-methyl-2-(4-nitrophenyl)-5-methoxy-6,7-dichloro-1-indanone which melts at 179°-180° C. after crystallization from butyl chloride
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:9][N:10]2[CH:14](OCC)[CH2:13][CH2:12][C:11]2=O)=[CH:4][CH:3]=1.[CH2:27](O)[CH3:28]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C:19]3[C:24](=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:12][CH2:11][N:10]4[CH2:28][CH2:27][CH2:5][CH2:8][CH2:9]4)[CH:20]=3)[C@H:11]3[CH2:12][CH2:13][CH2:14][N:10]3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC1CCC(=O)N1CC(c1ccc(Br)cc1)c1cccc(OC)c1
Reactant: CCO
Solvent: CCOC(C)=O
Product: Brc1ccc([C@@H]2CN3CCC[C@@H]3c3ccc(OCCCN4CCCCC4)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of 1-[2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-5-ethoxy-pyrrolidin-2-one (472.2 mg, 1.13 mmol) and MSA (2 N in ethanol, 10 mL) was stirred for 2 h at rt. The mixture was diluted with EtOAc, washed with satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated to give a colorless oil. Chromatographic purification (EtOAc/hexanes) yielded 325.4 mg (78%) of the desired product as a mixture of cis and trans diastereomers. The diastereomers were separated by normal-phase HPLC.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH2:31]([CH:30]([CH2:33][CH3:34])[CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH3:32]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)CN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 25 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 3-bromomethylpentane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Beat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2324, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.9 min, 100% purity.