Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:48])[CH2:46][NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:45](=[O:48])[CH2:46][NH2:47])=[O:16])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: NCC(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NCC(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 34.2 %

Procedure:
Using the procedure described in example 3, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (104.6 mg, 0.36 mmol, 1.0 eq), triethylamine (150 uL, 1.07 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (51 uL, 0.39 mL, 1.1 eq), then with glycine N-benzylamide (88.2 mg, 537 umol, 1.5 eq). Workup as before provided 53.9 mg (34%) of glycine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide. as a white foam.
Reaction SMILES: FC(F)(F)C(O)=O.O1CCCCC1[N:14]1[C:22]2[CH:21]=[CH:20][C:19]([O:23]C3CCCCO3)=[C:18]([C:30]#[N:31])[C:17]=2[CH:16]=[N:15]1.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[OH:23][C:19]1[CH:20]=[CH:21][C:22]2[NH:14][N:15]=[CH:16][C:17]=2[C:18]=1[C:30]#[N:31]
Reactant: N#Cc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1c(O)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
Trifluoroacetic acid (1.5 ml) was added dropwise to a solution of 1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole-4-carbonitrile (227 mg, 0.693 mmol) in dichloromethane (6.5 ml) at room temperature, and the resulting mixture was stirred for 1.5 hours while being maintained at room temperature. The reaction solution was diluted with ethyl acetate and adjusted to pH 7 with a saturated aqueous sodium hydrogencarbonate solution, followed by partition and extraction. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-hydroxy-1H-indazole-4-carbonitrile (108 mg, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].C1C(=O)N([Br:28])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:28][C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([CH3:20])([S:16]([CH3:19])(=[O:17])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C#Cc1ccc(CCC(C)(C(=O)OC)S(C)(=O)=O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C(C)(CCc1ccc(C#CBr)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 4.7 %

Procedure:
To a stirring solution of methyl 4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49 g, 8.46 mmol) and silver nitrate (144 mg, 0.85 mmol) in acetone (24 mL) was added NBS (2.5 g, 14.33 mmol) and the reaction was stirred at room temperature for 1.5 hr. Solvent was removed under reduced pressure to give a residue, which was purified by flash chromatography (silica gel/30-50% EtOAc/hexanes) to yield methyl 4-(4-(bromoethynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.6, 150 mg, 0.40 mmol, 4.75%). MS: m/z calcd for C15H17BrO4S 372.0/374.0. found [M+H]+ 373.0/375.0.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[Br:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[Cl:33]>ClCCl>[Br:25][C:26]1[N:31]=[C:30]([NH:32][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:29]=[CH:28][C:27]=1[Cl:33]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Nc1ccc(Cl)c(Br)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reaction time: 16 h
Yield: 69.4 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (0.878 g, 3.37 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Dichloromethane (10 mL), triethylamine (1.42 mL, 10.1 mmol) and 6-bromo-5-chloropyridin-2-amine (10.1 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction mixture was then washed with a saturated aqueous solution of sodium chloride, evaporated to near dryness, and then purified on 40 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.01 g, 69%). ESI-MS m/z calc. 429.9. found; 431.3 (M+1)+ Retention time 2.33 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2ccccc12
Yield: 78.3 %

Procedure:
Ethyl 2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate (4.9 g) was dissolved in ethyl acetate (200 ml) and 10% palladium-carbon (0.5 g) was added. The mixture was stirred with hydrogen (60 kg/cm2) at 60° C. for 5 hr. The reaction mixture was cooled and the catalyst was filtered off. The filtrate was evaporated under reduced pressure to give ethyl 2-(2-aminoanilino)benzo[b]thiophene-3-carboxylate (3.5 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:24]2[S:46][C:27]3=[N:28][C:29]([N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)=[CH:30][C:31](=[O:32])[N:26]3[N:25]=2)[CH:16]=[C:17]([C:19]([OH:23])(C)[CH2:20]O)[CH:18]=1)=[O:11])=O)(C)(C)C.O>C1COCC1>[C:19]([C:17]1[CH:18]=[C:13]([NH:12][C:10](=[O:11])[CH2:9][NH2:8])[CH:14]=[C:15]([C:24]2[S:46][C:27]3=[N:28][C:29]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:30][C:31](=[O:32])[N:26]3[N:25]=2)[CH:16]=1)(=[O:23])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)cc(C(C)(O)CO)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(NC(=O)CN)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(2-(3-(2-(tert-butoxycarbonylamino)-acetamido)-5-(1,2-dihydroxypropan-2-yl)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (27.0 mg, 0.041 mmol) in THF (0.5 ml)/Water (0.500 ml) is added NaIO4 (17.5 mg, 0.082 mmol). The mixture is stirred at room temperature for 2 h and then extracted with EtOAc (2×10 ml). The combined organic layers are washed with brine and dried over Na2SO4. After the removal of organic solvent in vacuo, the crude product (26 mg) is directly used without further purification for the next step as described in Step 6 of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.CN(C)C=[O:19]>>[CH2:11]([O:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:13]1[O:15][CH2:14]1
Reactant: CN(C)C=O
Reactant: BrCC1CO1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(OOCC2CO2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
4-Fluorophenol (3.0 g) was dissolved in dimethylformamide (50 ml), then sodium hydride (1.28 g, 50%) was added thereto, and the mixture was stirred for 45 minutes in an ice bath. Epibromohydrin (2.3 ml) was added to the reaction mixture, and the mixture was stirred for 3 hours in the ice bath. The organic layer was partitioned by adding water and diethyl ether, and the resulting organic layer was washed with water and brine, dried, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the free compound (3.4 g, 75%) of the title compound as a colorless oil.
Reaction SMILES: N(C(OCC)=O)=NC([O:5][CH2:6][CH3:7])=O.O[C@@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:75]CC(O)=O>O1CCCC1>[C:6]([S:75][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)(=[O:5])[CH3:7]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(OCCN1CCN(C(=O)[C@H]2C[C@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CS
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1C[C@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h

Procedure:
A solution of 421 mg of diethyl azodicarboxylate in 1.2 ml of tetrahydrofuran was added dropwise, whilst ice-cooling, to a solution of 1.21 g of (2R,4S)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine and 634 mg of triphenylphosphine in 8 ml of tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 10 minutes. 171 μl of mercaptoacetic acid were then added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. Following the same procedure as described in Preparation 57(ii), the reaction mixture was worked up and purified, to give 1.04 g of the title compound, as a colorless powder.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[C:17](=O)([O-:38])[O:18][C:19]1C(C)=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=CN=1.[C:40]1([C:46]2[CH:51]=[CH:50][C:49](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O.C1COCC1>[OH:11][C@@H:6]([C:7]([CH3:8])([CH3:10])[CH3:9])[C@@H:2]([N:1]([C:49]1[CH:48]=[CH:47][C:46]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:51][CH:50]=1)[C:17]([O:18][CH3:19])=[O:38])[C:3]([OH:5])=[O:4]
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccnc1OC(=O)[O-]
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccn(C(=O)[O-])c1=O
Reactant: CC(C)(C)[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@@H](O)C(C)(C)C
Reaction time: 15 h
Yield: 32 %

Procedure:
To a stirred diastereomeric mixture containing (2R*,3R*)- and (2R*,3S*)-2-amino-3-hydroxy-4,4-dimethyl-pentanoic acid (0.288 g, 1.78 mmol) and NaHCO3 (0.15 g, 1.8 mmol) in H2O (7.0 mL), at rt, the isomeric mixture containing (4-phenylphenyl)-methyl-2-pyridyl carbonate and (4-phenylphenyl)-methyl-2-oxopyridine-1-carboxylate (0.82 g, 2.68 mmol) [prepared as for example 17, step 1] in THF (7.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.21 g, 32% over 2 steps), as a diastereoisomeric mixture (anti:syn=9:1), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 410 [M−K]+; (ESI) m/z: 370 [M−H]−. 1H NMR (DMSO-d6) δ 0.88 (s, 9H), 3.40 (d, J=7.37 Hz, 1H), 4.09-4.18 (m, 1H), 5.08 (s, 2H), 5.08 (s, broad, 1H), 7.33-7.53 (m, 5H), 7.60 (d, J=8.97 Hz, 1H), 7.63-7.72 (m, 4H), 12.21 (s, 1H) (reported data refer to the major anti diastereoisomer).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH2:4][OH:5].Cl[C:8](OC1C=CC([N+]([O-])=O)=CC=1)=[O:9].C(N(CC)C(C)C)(C)C.[C:29]1([C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:35]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:36]=[CH:37][C:38]([CH2:39][NH:40][C:8](=[O:9])[O:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6])=[CH:41][CH:42]=1
Reactant: CNC(=O)CO
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COC(=O)NCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.1 g (0.97 mmol) of N-methyl-2-hydroxyacetamide is admixed dropwise at ambient temperature with a solution of 0.196 g (0.97 mmol) of 4-nitrophenyl chloroformate in 3 ml of methylene chloride and 0.166 ml (0.97 mmol) of N,N-diisopropylethylamine. The mixture is stirred at ambient temperature for 45 minutes and then a solution of 0.195 g (1.067 mmol) of 4-phenylbenzylamine in 3 ml of methylene chloride and 0.166 ml (0.97 mmol) of N,N-diisopropylethylamine is added dropwise at ambient temperature. The mixture is stirred at ambient temperature for 1 hour. It is washed with saturated aqueous ammonium chloride solution, with aqueous 10% sodium carbonate solution and with saturated aqueous sodium chloride solution. The phases are separated and the organic phase is dried over sodium sulphate. The system is filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel using ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[C:38]3[C:33](=[C:34]([F:40])[C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[C:38]2[C:33]=1[CH2:32][CH2:31][N:30]2[C:28]([C:24]1[CH:23]=[C:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:27]=[CH:26][N:25]=1)=[O:29]
Reactant: O=C(c1cc(Cl)ccn1)N1CCc2c1ccc(F)c2F
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)N4CCc5c4ccc(F)c5F)c3)CC1)C(=O)N2

Procedure:
0.18 g (0.67 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.20 g (0.68 mmol) (4-chloro-pyridin-2-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone and 97 mg (0.70 mmol) potassium carbonate were stirred in 3 mL of NMP for 4 h at 130° C. and overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH:1]1([CH:4]([OH:19])[C@H:5]2[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([C:4]([C@H:5]2[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:19])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(O)C2CC2)COC1(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)C2CC2)COC1(C)C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of (R)-tert-butyl 4-(cyclopropyl(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 230, 12.47 g, 45.95 mmol) in DCM (300 mL) at room temperature was added Dess-Martin periodinane (29.2 g, 68.93 mmol). The reaction mixture was stirred overnight then diluted with ethyl acetate and washed with saturated sodium bicarbonate. An emulsion formed and was filtered through celite. The layers were separated and the organics washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound as a colorless oil (11.15 g, 90%).
Reaction SMILES: [CH:1]1[C:10]2[CH:11]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][CH:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[CH:11]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3cccc4c3N(CCC4)C2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)C1CCNCCC1N3CCC2
Temperature: 20 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of tert-butyl (±)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate in CH2Cl2 (2.4 mL) was added TFA (0.6 mL). This was stirred at 20° C. for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow oil (87 mg, 59%). 1H NMR (CDCl3, 300 MHz) δ1.77-2.13 (m, 7H), 2.56-2.79 (m, 5H), 2.83-2.93 (m, 1H), 3.00-3.16 (m, 2H), 3.33-3.41 (td, 1H, J=3.7, 9.2 Hz), 3.60 (td, 1H, J=4.4, 9.1 Hz), 6.50 (t, 1H, J=7.3 Hz), 6.76 (t, 2H, 8.0 Hz) ppm.
Reaction SMILES: O1CCOCC1.[CH2:7]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:30]=2)[CH:16]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C(OCC)(=O)C.CO>[CH2:7]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:30]=2)[CH:16]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1cccc(-n2cccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1cccc(-n2cccc2)c1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To dioxane 2.0 mL solution of tert-butyl 4-phenethyl-2-(3-(1H-pyrrol-1-yl)phenylamino)benzoate 83 mg were added methanol 2.0 mL and 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL, and it was heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-phenethyl-2-(3-(1H-pyrrol-1-yl)phenylamino)benzoic acid 36 mg of a white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH:18]([F:20])[F:19])[C:11]([CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1)=[C:10]2[O:28][CH:29]([F:31])[F:30].[F:32][C:33]1[CH:49]=[CH:48][C:36]([C:37]([CH:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[O:38])=[CH:35][CH:34]=1>C1COCC1>[F:19][CH:18]([F:20])[O:17][C:12]1[C:11]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[C:10]([O:28][CH:29]([F:31])[F:30])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:37]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:49][CH:48]=3)([OH:38])[CH:39]3[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]3)[CH:8]=2)[N:13]=1
Reactant: FC(F)Oc1nc2ccc(Br)cc2c(OC(F)F)c1Cc1cncnc1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc3nc(OC(F)F)c(Cc4cncnc4)c(OC(F)F)c3c2)CC1
Reaction time: 0.17 h

Procedure:
n-BuLi (1.6 M in THF, 0.26 mL, 0.41 mmol) was added dropwise over a 1 minute period to a mixture of 6-bromo-2,4-bis(difluoromethoxy)-3-(pyrimidin-5-ylmethyl)quinoline (0.16 g, 0.37 mmol, Intermediate 50) and 1-(4-(4-fluorobenzoyl)piperidin-1-yl)ethanone (0.10 g, 0.41 mmol, Intermediate 44) in dry THF (3.8 mL) at −78° C. Stirring was continued at −78° C. for 10 minutes. The reaction mixture was then placed in an ice bath and stirred at 0° C. for 1 hour. The reaction was then quenched with aqueous NH4Cl, diluted with water and extracted with EtOAc (2×). The EtOAc extracts were dried over Na2SO4, filtered, evaporated in vacuo and purified by FCC (0-10% MeOH in DCM, gradient) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.00-9.19 (m, 1H), 8.61-8.79 (m, 2H), 8.05-8.22 (m, 1H), 7.69-7.93 (m, 3H), 7.37-7.56 (m, 2H), 6.93-7.13 (m, 2H), 6.36-6.89 (m, 1H), 4.59-4.83 (m, 1H), 4.20 (s, 2H), 3.67-3.97 (m, 1H), 2.95-3.23 (m, 1H), 2.43-2.83 (m, 2H), 2.04 (s, 3H), 1.61-1.79 (m, 1H), 1.30-1.51 (m, 3H); MS (ESI) 603 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][Cl:12].[N:14]([O-])=O.[Na+]>Cl.O>[Cl:12][CH2:11][CH2:10][CH2:9][C:8]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][N:14]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1C(=O)CCCCl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: ClCCCc1n[nH]c2ccccc12
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a suspension of 1-(2-aminophenyl)-4-chloro-1-butanone (508 mg, 2.6 mmol) in concentrated HCl (3.5 mL) at −5° C. was added a solution of NaNO2 (193 mg, 2.8 mmol) in H2O (0.75 mL), and the reaction mixture was stirred for 1 h. A solution of SnCl2-2H2O (1.37 g, 6.07 mmol) in concentrated HCl (1.9 mL) was added at −5° C. to the solution, and this stirred for 1 h under ice cooling. The reaction was quenched with H2O and extracted into Et2O (100 mL). The organic solution was washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography afforded 3-(3-chloropropyl)-1H-indazole (126 mg, 25%) as a yellow solid. The title compound was isolated as a yellow oil (38 mg, 77%) according to the method of Example 286, Step C from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 3-(3-chloropropyl)-1H-indazole (44 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.83-2.19 (m, 7H), 2.23-2.35 (m, 1H), 2.43-2.54 (m, 2H), 2.72-2.79 (m, 1H), 2.81-2.88 (m, 1H), 2.92-3.11 (m, 4H), 3.12-3.21 (m, 1H), 3.24-3.29 (m, 1H), 3.51-3.62 (m, 1H), 3.80-3.92 (m, 1H), 6.61 (t, 1H, J=7.5 Hz), 6.84 (d, 1H, J=6.6 Hz), 6.94 (dd, 1H, J=1.1, 7.7 Hz), 7.11-7.16 (m, 1H), 7.34-7.48 (m, 2H), 7.70 (d, 1H, J=8.0 Hz) ppm.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:19])=[O:18]
Reactant: OCCC1CCOC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CCOC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-(Tetrahydro-3-furanyl)ethanol (230 mg) was dissolved in dry DCM (5 mL) and triethylamine (0.552 mL) was added. The stirred solution was cooled (ice bath) under nitrogen and methanesulphonyl chloride (0.199 mL) was added dropwise over 5 mins. The mixture was allowed to warm slowly to room temperature as the ice bath melted and was left for 16 h. The mixture was shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (364 mg).