Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH2:17][CH2:18][O:19][CH3:20])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([C:35](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>ClCCl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:35]([NH:16][C:10]2[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:6]3[C:5]([F:21])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH2:17][CH2:18][O:19][CH3:20])[N:9]=2)([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:41][CH:40]=1
Reactant: COCC[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC[C@]1(c2nc(Br)ccc2F)N=C(NC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)OCC1(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of (R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-(2-methoxy-ethyl)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (200 mg, 0.543 mmol) and triethylamine (110 mg, 1.087 mmol) in dichloromethane (5.4 ml) was added solid 4,4′-dimethoxytrityl chloride (202 mg, 0.598 mmol) under argon atmosphere. The green solution was stirred at rt for 16 hrs and was then evaporated in vacuo. The crude product was taken up with ethyl acetate and washed with aqueous citric acid, aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product (380 mg) was chromatographed over silica gel (Redisep column 12 g, cyclohexane/ethyl acetate 8:2) to give the title compound as a colourless foam. 339 mg (93% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[F:17][C:18]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:24]4[CH2:23][CH2:22][CH:21]([CH2:20][C:19]5[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:18]=5[F:17])[CH2:26][CH2:25]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: COc1ccc(F)c(CC2CCNCC2)c1
Product: COc1ccc(F)c(CC2CCN([C@H]3CC[C@H](c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
4-(1,3-Benzodioxol-5-yl)cyclohexanone and 4-(2-fluoro-5-methoxybenzyl)piperidine were reacted as described in in example 9 to give the product (31%, mp: 89°-91° C.). Calc'd for C25H29F2NO2 : C, 72.61%; H, 7.07%; N, 3.39%. Found: C, 72.66%; H, 7.07%; N, 3.30%.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[N:16]1([C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: CC(=O)N1CCN(c2ccc(-n3ccnc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1cn(-c2ccc(N3CCNCC3)cc2)cn1
Yield: 93.5 %

Procedure:
To 15.2 g of 1-acetyl-4-(4-imidazol-1-ylphenyl)-piperazine, 100 ml of concentrated hydrochloric acid was added, followed by heating at reflux for 3 hours. After the completion of the reaction, the reaction solution was cooled and then neutralized with an aqueous 1N sodium hydroxide solution, thereby to precipitate a crystal. The resulting crystal was filtrated, washed with a small amount of water and then dried to obtain 12 g of the objective 1-(4-imidazol-1-ylphenyl)-piperazine (melting point: 177-180° C.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](O)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([Cl:20])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
246 mg (0.766 mmol) of [4-(bromomethyl)phenyl](cyclopentyl)acetic acid were dissolved in 5 ml of thionyl chloride, and the mixture was stirred at room temperature for 1 h and then at 50° C. for 1 h. The mixture was then concentrated under reduced pressure. This gave 253 mg of the title compound, which was reacted without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:15]1([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (R)-3-(tert-butoxycarbonylamino)piperidine (0.10 g, 0.50 mmol), phenylboronic acid (0.13 g, 1.1 mmol) and copper (II) acetate (0.10 g, 0.551 mmol) in DCM (2 ml) under air was charged with triethylamine (0.14 ml, 1.0 mmol), sealed and stirred at RT for 18 hours followed by stirring at 60° C. for 72 hours. The reaction mixture was filtered through celite and eluted with DCM/MeOH. The filtrate was concentrated in vacuo and purified by flash chromatography (Biotage, 0-20% MeOH/DCM) to provide tert-butyl [(3R)-1-phenylpiperidin-3-yl]carbamate.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[OH-].[K+].[CH3:18][C:19](=[O:22])[CH:20]=[CH2:21]>CCO>[O:22]=[C:19]1[CH2:20][CH2:21][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (10.0 g, 46.9 mmol) and KOH (1.3 g, 23.5 mmol) in EtOH (200 mL) was added but-3-en-2-one (3.9 g, 56.3 mmol), the mixture was stirred at 70° C. for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/4) to give the product as brown oil (5.2 g, 41.8%).
Reaction SMILES: [CH3:1][CH:2]([C:12]([CH3:14])=[O:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4].[N+](=[CH2:17])=[N-]>>[CH3:17][O:13]/[C:12](/[CH3:14])=[C:2](/[CH3:1])\[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)C(C)C(=S)Nc1ccccc1
Product: CO/C(C)=C(/C)C(=S)Nc1ccccc1

Procedure:
2-methylthioacetoacetanilide [formed from α-chloroacetoacetanilide and sodium methylmercaptan] was reacted with diazomethane to obtain 3-methoxy-2-methylthio-crotonanilide melting at 155° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=O)(C)(C)C.O1CCO[CH2:19][CH2:18]1.[ClH:23]>>[ClH:23].[CH2:18]([O:16][C:14](=[O:15])[CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(=O)O
Reactant: C1COCCO1
Agent: Cl
Product: CCOC(=O)C[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 2 N hydrogen chloride in dioxane (250 mg, 1.1 mmol) in 4 N hydrogen chloride in dioxane (2 ml, 8 mmol) was stirred for 2 h at 25° C. and evaporated to dryness and redissolved in ethanol. After addition of a few drops of 12 M aqueous hydrochloric acid the mixture was stirred at 25° C. overnight. Solvents were evaporated to give 200 mg (95%) of (R)-pyrrolidin-2-yl-acetic acid ethyl ester hydrochloride (25 mg, 55%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[N:3]=1.[Na+].[I-].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH3:13].C(N(C(C)C)C(C)C)C>CCO>[CH3:9][NH:8][C:4]1[N:3]=[C:2]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH2:12][CH3:13])[CH2:19][CH2:18]3)=[CH:26][CH:25]=2)[N:7]=[CH:6][N:5]=1
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: CNc1ncnc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCN1CCN(c2ccc(Nc3ncnc(NC)n3)cc2)CC1
Temperature: 80 °C

Procedure:
A mixture of (4-chloro-[1,3,5]triazin-2-yl)-methyl-amine (290 mg, 2.00 mmol), NaI (28 mg) and 4-(4-ethylpiperazin-1-yl)-aniline (410 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350 μl, 2.0 mmol) is heated to 80° C. for 3 h under a nitrogen atmosphere. The reaction mixture is cooled to RT, concentrated partially in vacuo and diluted with hexane at 0° C. The precipitate is filtered off, washed with Et2O and re-dissolved in EE and water. The separated off aqueous phase is extracted twice with EE, the organic layer washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: ESI-MS: 314 [MH]+; TLC: Rf=0.10 (DCM/MeOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:34][O:35]/[N:36]=[C:37](\[CH:40]1[CH2:42][CH2:41]1)/[CH2:38][NH2:39]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:39][CH2:38]/[C:37](/[CH:40]3[CH2:42][CH2:41]3)=[N:36]/[O:35][CH3:34])=[O:16])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])=[CH:4][CH:3]=1
Reactant: CO/N=C(/CN)C1CC1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(/CNC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1)C1CC1
Yield: 45.5 %

Procedure:
To a suspension of (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)-pyrazine-2-carboxylic acid (0.2 g, 577 μmol, Eq: 1.00) in dimethylformamide (4 ml) were added under argon TBTU (204 mg, 635 μmol, Eq: 1.1), ethyldiisopropylamine (373 mg, 478 μl, 2.88 mmol, Eq: 5) and (E)-2-amino-1-cyclopropylethanone O-methyl oxime hydrochloride (104 mg, 635 μmol, Eq: 1.1) and the mixture was stirred at room temperature for 18 h overnight. The reaction mixture was partitioned between ethyl acetate and 10% aqueous citric acid, the phases were separated and the organic phase was dried over MgSO4; filtered; concentrated and purified by flash chromatography (silica gel, 20 g, 5% to 50% ethyl acetate in heptane) to yield the title compound as white crystals (0.12 g, 45.5%, m.p.: 149-152° C.). MS (EI): 457.1 (M+H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=[O:7].[CH2:11]([C:13]1([CH2:28][CH2:29][OH:30])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH2:15][O:14]1)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][CH3:27])[CH3:12]>C(Cl)Cl.[NH4+].[Cl-]>[CH2:11]([C:13]1([CH2:28][CH:29]([OH:7])[OH:30])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH2:15][O:14]1)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][CH3:27])[CH3:12]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(O)O)OCC3
Temperature: 0 °C
Yield: 31.8 %

Procedure:
Dry DMSO (71 μL, 1.0 mmol, 2.0 eq) was added dropwise to a solution of oxalyl chloride (66 μL, 0.75 mmol, 1.5 eq) in CH2Cl2 (1 mL) at −78° C. After stirring for ten minutes, a solution of compound 1 (136 μL, 0.5 mmol) in CH2Cl2 (4 mL) was added dropwise, and the reaction was stirred for an additional thirty minutes at −78° C. before the addition of TEA (2.79 μL, 2.0 mmol, 4.0 eq). The reaction mixture was then allowed to warm slowly to 0° C., diluted with saturated NH4Cl, and extracted twice with Et2O. The combined organic phases were washed with water and brine, dried with Na2SO4, concentrated, and purified by column chromatography using a gradient of 50:50:EtOAc:Hexane to 100% EtOAc to give a white solid (46 mg, 32%): mp 158–159° C. 1HNMR (CDCl3, δ TMS): 0.50 (t, 3H), 1.25 (t, 3H), 1.50 (m, 1H), 1.82 (m, 1H), 2.04 (m, 1H), 2.17 (m, 1H), 2.33 (m, 1H), 2.58 (q, 2H), 2.88 (m, 2H), 3.77 (m, 1H), 3.91 (m, 1H), 4.19 (q, 1H), 4.33 (m, 1H), 7.02–7.15 (m, 3H, Ar—H), 7.66 (br, 1H, NH). MS−: m/z 288 ([M−H]−). Anal. (C17H23NO3): C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C[NH:59][S:60]([CH:63]1[CH2:65][CH2:64]1)(=[O:62])=[O:61].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:59][S:60]([CH:63]([CH3:65])[CH3:64])(=[O:62])=[O:61])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C(C)C)CC5C=CCCCCN(C)C(=O)C4C3)nc(-c3cccc(F)c3)nc2c1C
Temperature: 50 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
A mixture of the acid 159 (71 mg, 0.115 mmol) and CDI (37 mg, 0.228 mmol) in dry THF (10 mL) was heated at reflux for 2 h under N2. The reaction mixture was cooled 50° C. and a pre-mixed solution of methyl-cyclopropyl sulfonamide (43 mg, 0.349 mmol) and DBU (49 μL, 0.322 mmol) in 2 ml of dry THF was added to the reaction mixture. The reaction was stirred at 50° C. for 18 h. The solvent was evaporated and the residue was dissolved in CHCl3 and washed with citric acid (10% aq). The organic phase was dried with Na2SO4, filtered and the solvent was removed by rotary evaporation. The crude product was purified by HPLC on an Ace-5 C8 column (100×21.2 mm) with a gradient going from 35 to 60% acetonitrile (0.1% TFA) in H2O (0.1% TFA) over 8 minutes. The product was obtained as a white solid (30 mg, 36%), LRMS (M+H) 722.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:49](=[O:50])[CH2:48][NH:47][C:45](=[O:46])[O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 480.4 %

Procedure:
5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.0103 mmol) was treated with N-{[(1,1-dimethylethyl)oxy]carbonyl}glycine (0.018 g, 0.103 mmol), DIPEA (0.090 mL, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) in a similar manner as described herein to afford crude 1,1-dimethylethyl {2-[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]-2-oxoethyl}carbamate (0.031 g) as an off-white solid. This material was treated with trifluoroacetic acid (0.30 mL, 3.89 mmol) in dichloromethane (1 mL) for 1 h. The solvent was evaporated to give the title compound (0.011 g, 40%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ ppm 11.60 (s, 1H), 10.23 (s, 1H), 8.97 (s, 1H), 8.04 (m, 3H), 7.91 (s, 1H), 7.77 (s, 1H), 7.40-7.54 (m, 2H), 7.29-7.40 (m, 2 H), 7.17-7.27 (m, 1H), 7.10 (s, 1H), 4.60 (s, 2H), 3.72 (s, 2H). MS: m/z 526 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[CH2:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cl[C@H]1CCCN(CCc2ccccc2)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.8 %

Procedure:
Sixty-percent sodium hydride (608 mg, 15 mmols) was washed with petroleum ether, and then suspended in 50 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.6 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 1 hour. To this reaction solution was added dropwise a solution of 3.2 g (14 mmols) of (S)-(+)-3-chloro-1-phenethylpiperidine [[α]D25 =+10.9° (c=1.0, ethanol)] in 30 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 2.5 hours and at 45° C. for 6 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 3.5 g of (R)-(+)-5,11-dihydro-5-[1-phenethyl-2-pyrrolidinyl-methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 91%.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]1[CH2:48][CH2:47][S:46][C@@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]([O:55][CH3:56])=[O:54])[N:44]2[C:43]1=[O:57]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:15]([NH:17][C@@H:18]1[CH2:24][CH2:23][S:22][C@@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]([O:55][CH3:56])=[O:54])[N:44]2[C:43]1=[O:57])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: COC(=O)[C@@H]1CCC[C@H]2SCC[C@@H](N)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3CCS[C@@H]4CCC[C@@H](C(=O)OC)N4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((4R,7S,10aR)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (5.0 mg, 0.0088 mmol) and (4R,7S,10aR)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (2.2 mg, 0.0097 mmol) to give a white solid (3.2 mg, 40% yield). Anal. Calcd. for C42H54N4O8S2 m/z 806.4. found: 807.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[O:23][CH3:24]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
2-(Trifluoromethoxy)phenol (6.0 g, 32.7 mmol) was dissolved in methylene chloride and triethylamine (9.1 mL, 65.4 mmol). The mixture was cooled to 0° C. and methyl chloroformate (2.8 mL, 36.0 mmol) was added dropwise. The mixture was stirred for 2 h at room temperature then quenched with saturated NH4Cl. The reaction was diluted with water and the aqueous layer extracted with dichloromethane (2×30 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to provide methyl 2-(trifluoromethoxy)phenyl carbonate (7.1 g, 92% yield). 1H NMR (400.0 MHz, DMSO-d6) δ7.36-7.26 (m, 4H), 3.93 (s, 31-1).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[F:17].[Li+].[OH-].O1CCCC1.Cl>O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[F:17]
Reactant: CCOC(=O)CCCOc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCOc1ccc(Br)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed ethyl 4-(4-bromo-3-fluorophenoxy)butanoate (80.6 g, 264.14 mmol, 1.00 equiv), LiOH (12.7 g, 530.27 mmol, 2.00 equiv), tetrahydrofuran (250 mL), and water (240 mL). The resulting solution was stirred at 50° C. overnight, cooled to 0° C. with a water/ice bath, adjusted to pH=3-4 with hydrochloric acid (2 N) and extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated in 30 mL of EA to afford 50 g (68%) of 4-(4-bromo-3-fluorophenoxy)butanoic acid as a white solid.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([N:12]1[C:20]2[C:15](=[C:16]([CH2:21]O)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C([O-])(O)=O.[Na+]>CCOCC.C(Cl)Cl>[Br:2][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]2[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)n1ccc2c(CO)cccc21
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc2c(CBr)cccc21
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
PBr3 (2.4 mL. 25.8 mmol) was added dropwise at 0° C. under nitrogen to a stirred solution of tert-butyl 4-(hydroxymethyl) 1H-1-indolecarboxylate 6 (6.0 g, 24.3 mmol) in ether (80 mL) and CH2Cl2 (20 mL) under nitrogen. The reaction was completed 30 minutes after the addition. The mixture was poured into a cold aqueous NaHCO3 solution (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extract was washed sequentially with water (80 mL), and brine (80 mL), then dried (MgSO4), filtered, and finally concentrated to provide tert-butyl 4-(bromomethyl)-1H-1-indolecarboxylate 7 (6.3 g, 84%) as an oil which was immediately taken to the next step.