Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[H][H]>C(OCC)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOCC
Product: Nc1ccc2c(c1)C(=O)OC2=O
Temperature: 245 °C
Yield: 52.7 %

Procedure:
In 200 ml of dry ethyl ether, (C2H5)2O, was dissolved 1.93 g of 4-nitrophthalic anhydride (~1% solution) to which was added 0.10 g of 5% palladium-on-charcoal and the mixture hydrogenated in a Paar hydrogenator at 39 psi at room temperature, until no more hydrogen was consumed. The catalyst was removed by filtration and the ether removed from the filtrate, maintained at 0° to -5°C, under vacuo, yielding a yellow crystalline solid mixed with non-crystalline viscous mass. When a small sample of this mixture was placed on a metal plate heated to 245°C, the product melted and polymerized immediately to a tough polymer. Extraction of the crystalline-non-crystalline mixture with ether left 0.46 g of polymer; concentration of the ether followed by cooling, yielded 0.86 g of 4-aminophthalic anhydride.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH3:18][C:19]1([CH3:32])[CH2:24][NH:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[CH3:18][C:19]1([CH3:32])[CH2:24][N:23]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1(C)C
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (440 mg, 1.68 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (8 mL) was added 1,1-dimethylethyl 2,2-dimethyl-1-piperazinecarboxylate (359 mg, 1.68 mmol, commercially available, for example from ChemPacific Corp., Baltimore, USA) and triethylamine (0.701 mL, 5.03 mmol). The mixture was then heated to 120° C. for 20 minutes in a microwave reactor.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl.[Cl:10][C:11]1[CH:36]=[CH:35][C:14]2[O:15][C:16]3[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=3[C@@H:18]3[C@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1>CC(C)=O.C(OCC)(=O)C>[Br:1][C:36]1[C:11]([Cl:10])=[CH:12][C:13]2[N:19]3[CH2:20][CH2:21][CH2:22][C@@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C@H:18]3[C:17]3[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=3[O:15][C:14]=2[CH:35]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(Br)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 130.3 %

Procedure:
N-bromosuccinimide (9.2 mg, 0.05 mmol) and 0.5 μL of 1N HCl were added to trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (20 mg, 0.05 mmol) in 512 μL of acetone. The resulting mixture was stirred at room temperature for 30 min. The mixture was diluted with ethyl acetate, washed with saturated aq. sodium bicarbonate and water, dried (Na2SO4) and evaporated to give trans-N-(8-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide as a white solid (31 mg, 100%). Data: 1H-NMR (400 MHz, CDCl3) 1.85 (m, 4H), 2.27 (m, 2H), 3.20 (m, 1H), 3.64 (m, 1H), 4.44 (d, J=8.0, 1H), 4.65 (m, 1H), 6.26 (b, 1H), 7.02 (s, 1H), 7.10 (dt, J=8.0, 2.0, 1H), 7.16 (m, 2H), 7.30 (dt, J=8.0, 3.0, 1H), 7.35 (s, 1H). (m/z)=477 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.Cl.Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([C:31]5[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=5)[CH2:22][CH2:23]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(c4ccncc4)CC3)ccc2n1CC1CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(cyclopropylmethyl)-2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazole (STEP D, 25 mg, 0.062 mmol), 4-chloropyridine hydrochloride (19 mg, 0.12 mmol) and triethylamine (35 microL, 0.25 mmol) in ethanol was stirred at 150° C. under microwave for 3 h. The solvent was removed. The residue was diluted with ethyl acetate and saturated sodium bicarbonate aqueous solution to separate. The aqueous layer was extracted with ethyl acetate (3 mL×2) and the organic layer was filtered through magnesium sulfate column. The filtrate was concentrated in vacuo. The residue was purified by prep-LC-MS (“process A”).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(O)C.[OH-].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][CH:16]=1)=[O:14])[CH3:11]>C(OCC)(=O)C>[N+:1]([CH2:4][CH:23]([OH:24])[CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(CCC(O)C[N+](=O)[O-])cc1
Temperature: 38 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a stirred mixture of 2.25 (37 mmol) of nitromethane, 1.2 mL of ethanol and 0.06 mL of 10N aqueous sodium hydroxide solution was added 7.18 g (37 mmol) of 3-(4-ethoxycarbonylphenyl)-1-propanal at room temperature. After addition of the aldehyde, 0.06 mL of 10N aqueous sodium hydroxide and 0.23 mL of ethanol were added, and the resulting mixture was stirred at 38° C. for 48 hours and then poured into a mixture of ethyl acetate (100 mL) and hexanes (100 mL). The resulting solution was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 1:4 ethyl acetate:hexanes, to afford 4.1 g (72%) of 1-nitro-4-(4-ethoxycarbonylphenyl)-2-butanol as a white solid, IR (KBr) 3439, 2929, 1700, 1619, 1553, 1362, 1289, 1180, 1137, 1105, 1019, 882, 739 cm-1. 1H NMR (CDCl3) δ 7.98 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.0 Hz), 4.42 (2H, d, J=5.5 Hz), 4.38 (2H, q, J=7.0 Hz), 4.34-4.29 (1H, m), 3.03 (1H, br s), 2.96-2.90 (1H, m), 2.84-2.78 (1H, m), 1.92-1.78 (2H, m), 1.40 (3H, t, J=7.0 Hz); 13C NMR (CDCl3) 8166.86, 146.36, 130.05, 128.70, 128.61, 80.76, 67.85, 61.15, 34.99, 31.50, 14.46; EIMS m/z 267 (M+), 265, 252, 249, 232, 222, 206, 177, 161, 149, 133, 105, 91, 77; HRMS calc'd for C13H17NO5 267.1107, found 267.1095.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Cl.[Br:31]C1C=C2C(C=C(C(O)=O)N2)=CC=1OC1CCN(C(C)C)CC1.BrC1C=C2C(C=C(C(N3CCOCC3)=O)N2C2C=CN=C(Cl)C=2)=CC=1OC1CCN(C(C)C)CC1>>[Br:31][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:8]([N:5]3[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]3)=[O:9])[NH:11]2)=[CH:16][C:15]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride salt with 1 eq. lithium chloride (example 41, step 5). The title compound was obtained in 77% yield as light yellow solid. MS (m/e): 486.2 (MH+, 100%).
Reaction SMILES: [C:1]([C@H:5]([NH:27][CH2:28][C:29]([O:31]CC)=O)[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35]>C1COCC1>[C:1]([C@H:5]([NH:27][CH2:28][C:29]([NH:36][CH2:34][CH3:35])=[O:31])[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C

Procedure:
A solution of ethyl ({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)acetate (7-1, 50 mg, 0.11 mmol) in a solution of ethylamine in THF (2 M, 2 mL) was heated in a sealable tube at 100° C. for 16 h. The reaction mixture was concentrated and the residue purified by flash column chromatography (EtOAc) to give 2-({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)-N-ethylacetamide (7-2) as a white solid. 1H NMR (500 MHz, CDCl3) showed a 1:1 mixture of rotamers; one rotamer: δ 7.43-7.22 (m, 5H), 7.11-6.96 (m, 3H), 6.89 (br m, 1H), 6.38 (br s, 1H), 5.94 (m, 1H), 4.92 (ddd, 1H, J=14.9, 4.4, 1.7 Hz), 4.87 (br d, 1H, J=15.3 Hz), 3.42 (d, 1H, J=16.8 Hz), 3.35 (m, 2H), 3.03 (s, 1H), 2.88 (d, 1H, J=16.8 Hz), 2.34 (br s, 1H), 1.18 (t, 3H, J=7.3 Hz), 1.06 (s, 9H). LRMS m/z (M+H) 456.5 found, 456.2 required.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[O:22]1[C:26]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:25]=2[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=3)[NH:7][CH:6]=[C:5]4[CH:14]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]3)=[CH:30][C:25]=2[CH2:24][CH2:23]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc3c(c2)CCO3)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Reaction time: 0.3 h
Yield: 20.5 %

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (30 mg, 0.081 mmol), 2,3-dihydro-1-benzofuran-5-ylboronic acid (26.5 mg, 0.162 mmol), and K2CO3 (33.7 mg, 0.242 mmol) in 1,4-dioxane (0.36 mL) and water (0.180 mL) was degassed in a Biotage microwave vial for 10 min. PdCl2 (dppf) (5.91 mg, 8.08 μmol) was added, the vial was sealed, and the reaction was heated at 100° C. (bath temp) for 5 min in a Biotage microwave oven at high absorption. EtOAc (3 mL) and water (1 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4×2 mL). The combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), and concentrated under a stream of nitrogen at 50° C. The crude product was dissolved in DMSO (1.2 mL), filtered through a 0.2 mm acrodisc, and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C., giving 6.8 mg (20%) of the title compound.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCOCC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
To a solution of 3.368 g (10.22 mM) of 3-hexadecyloxy-2-methoxypropylamine IVa3 in 35 ml of dichloromethane and 1.85 ml (13.29 mM) of triethylamine is added 1.99 g (11.24 mM) of 3-chloropropanesulfonyl chloride with ice-cooling and the mixture is stirred at room temperature for 4 hours and then heated for 30 minutes with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:1) mixture as an eluent. The product is recrystallized form methanol to give 4.15 g (8.827 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecyloxy-2-methoxypropane IIIa3 as a colorless powder in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1>CN(C=O)C>[NH2:11][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1
Reactant: Nc1nc(Cl)nc2[nH]cnc12
Reactant: CCOP(=O)(Cc1ccc(CBr)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(Cl)nc32)cc1)OCC
Temperature: 60 °C
Yield: 18 %

Procedure:
To a solution of commercially available 2-chloro-9H-purin-6-amine (1 equiv.) in DMF (0.50 M) was added potassium carbonate (1.2 equiv.) and diethyl 4-(bromomethyl)benzylphosphonate (1 equiv.) (described in ref. 88, Ex 25 Step 1). The reaction mixture was then heated to 60° C. for 5 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system (ISCO) using a gradient of 0-5% MeOH/DCM to provide the title compound (18%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][C:16]=1[C:17]#[N:18].[C:19](Cl)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CCOC(C)=O.[Zn]>[C:19]([C:14]1[NH:13][C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[C:16]([C:17]#[N:18])[CH:15]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1cc[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(=O)Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C#N)c(-c2cc(C(F)(F)F)ccc2Cl)[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a mixture of 2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonitrile (450 mg, 1.66 mmol) in toluene (3 mL) was added acetyl chloride (0.176 mL, 2.49 mmol) at room temperature, under nitrogen, and zinc (217 mg, 3.32 mmol). The mixture was allowed to stir for 3 h at 80° C. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (0 to 10% EtOAc/hexane) to afford the title compound (386 mg, 74%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[Cl:14][C:10]1[CH:9]=[C:8]([N:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:15]([Cl:17])=[O:16])[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(Nc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(Cl)c1
Yield: 58 %

Procedure:
Following the procedure of Example 15, Step A, 20.4 g (100 mmole) of 3-chlorodiphenylamine [i.e., N-(3-chlorophenyl)aniline] and phosgene in toluene gave 15.4 g (58%) of N-(3-chlorophenyl)-N-phenylcarbamoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>>[CH3:22][O:21][C:19](=[O:20])[C@@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[O:36])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COc1ccc(N=C=O)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)cc2C1=O

Procedure:
The compound of example 27 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-methoxy phenyl isocyanate. The compound of example 27 was used directly without isolation for the preparation of compound of example 28.
Reaction SMILES: [CH:1]([C@H:4]([NH2:7])[CH2:5]O)([CH3:3])[CH3:2].[Cl-].ClC[C@@H]([NH3+])C(C)C.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[S:28]>>[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]1[NH:7][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][S:28]1
Reactant: CC(C)[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: CC(C)[C@H]([NH3+])CCl
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CS1

Procedure:
(1S)-1-Isopropyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1-isopropylethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-isopropylethylammonium chloride according to Method C1a to give (45)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].CCCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:39]3[CH2:38][CH2:37][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:35])[CH2:41][CH:40]=3)[CH:3]=[CH:4][C:5]=2[F:28])[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[N:11]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 88 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 1.06 mmol) prepared in Step 5 of Preparation 8, 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (26.7 mg, 1.59 mmol), Pd(PPh3)4 (123.0 mg, cat.) and a 2N sodium carbonate solution (5.0 mL) were added to a mixed solvent of ethanol (5.0 mL) and 1,2-dimethylethane (20.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give 360.0 mg of the titled compound as a white liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH2:27][C:28]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30][CH2:29]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2]>ClCCCl.C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][C:28]3([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[CH2:29][O:30][C:31]([CH3:34])([CH3:35])[O:32][CH2:33]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOc1ccc(-c2nc(-c3cccc4c3ccn4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Temperature: 50 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A suspension of the product of Example 34, Step D (0.07 g; 0.118 mmol), MnO2 (0.58 g; 6.67 mmol) and anhydrous MgSO4 (0.5 g; 4.2 mmol) in 1,2-dichloroethane (2.5 ml) was vigorously stirred for 2 h at ˜50° C., then overnight at room temperature. This was diluted to 20 ml with CH2Cl2 and filtered through Celite pad, washed with fresh CH2Cl2 (10 ml). The combined organic phase was evaporated under reduced pressure and the residue was purified by FCC (SiO2, CH2Cl2/EtOAc 9:1) to give the title compound (0.02 g; 28%), as creamy solid. 1H-NMR (CDCl3) 1.43-1.53 (m, 21H+H2O); 3.78 (d, 2H, J=11.9 Hz); 3.90 (d, 2H, J=11.9 Hz); 4.13-4.38 (m, 5H); 4.76 (s, 1H); 6.98 (d, 1H, J=8.5 Hz); 7.15 (s, 1H); 7.28-7.34 (m, 2H); 7.68 (d, 1H, J=8.4 Hz); 7.73 (d, 1H, J=1.9 Hz); 7.83 (dd, 1H, J=1.9, 8.4 Hz); 8.03 (d, 1H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:13]([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C#CCCCO[Si](C)(C)C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 4-pentyn-1-ol (25.0 g, 0.30 mole) in dry CH2Cl2 (250 ml) at 0° C., was added imidazole (40.46 g, 0.60 mole) and chlorotrimethylsilane (56.6 ml, 0.45 moles) and stirred for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×100 ml). Combined organic extracts were washed with water, brine, dried (Na2SO4) and the solvent was evaporated. Purification of the crude product by vacuum distillation afforded the pure ether 13 (44.1 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI.Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH3:11]
Reactant: Oc1c(Cl)cc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Cl)cc(Cl)cc1Br
Temperature: 0 °C
Yield: 113.1 %

Procedure:
2-Bromo-4,6-dichlorophenol (Preparation 24, 4.6 g, 19 mmol), potassium carbonate (4.5 g, 32.3 mmol) and methyl iodide (1.8 ml, 20.5 mmol) were combined in 46 ml acetone and heated to reflux for 18 hours. The reaction was cooled to 0° C., 1N HCl (aqueous) was added to give pH 3, and the reaction was extracted into 50 ml ethyl acetate. The organic layer was washed with brine (2×20 ml), dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown solid (5.5 g).