Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[N:14][N:13]2[CH:16]=[CH:17][N:18]=[C:12]2[CH:11]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:9][C:10]1[CH:15]=[N:14][N:13]2[C:16]([I:1])=[CH:17][N:18]=[C:12]2[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cnn2ccnc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cnn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
N-Iodosuccinimide (2.17 g, 9.65 mmol) was added to a solution of 7-chloroimidazo[1,2-b]pyridazine (0.988 g, 6.43 mmol) in N,N-dimethylformamide (25 mL). The reaction mixture was stirred at r.t. overnight. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (gradient: 0-50%) to afford the desired product (1.40 g, 77.9%). LCMS (M+H)+: m/z=279.9/281.9.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: N[C@H]1CCc2ccccc2NC1=O
Product: CC(C)(CC(=O)N[C@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3(S)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-on (Example 1, Step B) and 3-benzyloxycarbonylamino-3-methylbutanoic acid (Example 1, Step E) by the procedure described in Example 1, Step F. FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%). [a]D =-160° (C=1,CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13]/[N:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+]([C:26]([CH2:53][CH2:54][CH2:55][CH3:56])=[CH:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][C:29]=1[C:41]([N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])([O-])=O>>[C:35]([O:34][C:32]([C:31]1[CH:39]=[CH:40][C:28]([C:27]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=4)=[CH:12][CH:11]=3)[C:26]=2[CH2:53][CH2:54][CH2:55][CH3:56])=[C:29]([C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[CH:30]=1)=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: CCOC(=O)/C=N/Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 46.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-(4-chlorophenoxy)phenyl)hydrazono)acetate (41 mg, 0.13 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (60 mg, 0.13 mmol) were converted to the title compound (44 mg, 46%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.09 (dd, J=8, 2 Hz, 1H), 8.04-8.03 (m, 1H), 7.43-6.81 (m, 13H), 5.02-4.98 (m, 1H), 4.48-4.38 (m, 1H), 4.33-4.27 (m, 2H), 4.18-3.98 (m, 1H), 3.58-3.32 (m, 1H), 2.85-2.48 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.20 (t, J=8 Hz, 1.5H), 1.15-0.91 (m, 4H), 0.63-0.59 (m, 3H); MS(ESI+) m/z 734.2 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2-c1ccc(F)cc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(-c3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 423 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Li+].[CH3:19]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3]([C@:5]1([CH3:19])[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (1.13 g, 4.61 mmol) in THF (73 mL) at −78° C. was slowly added a 1.8 M solution of LDA (7.70 mL, 13.86 mmol). After stirring for 1 h, iodomethane (2.87 mL, 46.10 mmol) was added, and the reaction was stirred for 1 h at −78° C., before warming gradually to −20° C. for 3 h, and then was stored at −40° C. overnight. After quenching with saturated aqueous NH4Cl, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (Luna C-18, 21.2×250 mm, eluting with 50-90% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide a mixture of the starting material and its epimer as a yellow oil (490 mg) and the title compound as a yellow oil (362 mg); LC/MS m/z 260 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:16][CH2:17][C:18](Cl)=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC1(C)CNC(=O)CCl

Procedure:
A solution of tert-butyl 2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate (1.2 g), excess 2-chloroacetyl chloride (2 mL) and diisopropyl ethyl amine (2 mL) in DCM was stirred at room temperature for about 2 h. The reaction was monitored by LC-MS. After the solution was concentrated in vacuo, 0.7 g of the desired product was obtained by column chromatography purification. MS (ESI): 291, 293 (MH+).
Reaction SMILES: CC(N)(C)C[C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>CCO>[OH:20][C@@H:21]([CH2:22][N:30]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:16][CH:17]=1)[CH2:29][CH:37]([CH3:25])[CH3:36])[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 60 °C

Procedure:
4-(4-(2-Methyl-2-aminopropyl)phenoxy)phenol (0.40 g, 1.55 mmol) was combined with (S)-4-(oxiranylmethoxy)-9H-carbazole (0.250 g, 1.0 mmol) in EtOH (50 mL) and the mixture heated at 60° C. for 20 hours. The mixture was then concentrated in vacuo and the resulting residue chromatographed over silica (1-10% MeOH/CHCl3) which allowed for isolation of the product as the free base. The free base was then dissolved in minimal EtOAc and treated with diethyl ether (25 mL) saturated with HCl. Filtration and drying netted 0.410 g (76%) of product as the HCl salt. MS (FD+):497. m.p. 80-85° C. (dec). Anal. Calcd for C31H32N2O4.1.3HCl: C, 68.31; H, 6.16; N, 5.14. Found: C, 68.30; H, 6.75; N, 4.62.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([NH:17]C=O)([CH3:16])/[CH:5]=[CH:6]/[CH2:7][P:8]([O:13]CC)([O:10]CC)=[O:9].O>Cl>[NH2:17][C:4]([CH3:16])(/[CH:5]=[CH:6]/[CH2:7][P:8]([OH:13])([OH:10])=[O:9])[C:3]([OH:20])=[O:2]
Reactant: CCOP(=O)(C/C=C/C(C)(NC=O)C(=O)OC)OCC
Agent: Cl
Solvent: O
Product: CC(N)(/C=C/CP(=O)(O)O)C(=O)O

Procedure:
14.5 g of E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid methyl ester are heated for 32 hours under nitrogen at 100°-105° in 500 ml of 4.35 N hydrochloric acid. Working up as in Example 11 yields E-2-amino-2-methyl-5-phosphono-3-pentenoic acid, m.p. 225°-226° (from water).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH:6]([C:8]1[S:12][C:11]2[C:13](=[O:21])[C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19](=[O:20])[C:10]=2[CH:9]=1)[CH3:7]>ClCCCl>[C:1]([O:5][CH:6]([C:8]1[S:12][C:11]2[C:13](=[O:21])[C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19](=[O:20])[C:10]=2[CH:9]=1)[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Reactant: CC(=O)Cl
Solvent: ClCCCl
Product: CC(=O)OC(C)c1cc2c(s1)C(=O)c1ccsc1C2=O
Temperature: 0 °C
Yield: 74 %

Procedure:
Acetyl chloride (1.1 g, 13.6 mmol) was added to a solution of 10 (2.0 g, 7.4 mmol) in 1,2-dichloroethane (100 mL) and the mixture was refluxed for 4 h. After this time, the solution was poured into ice water. The organic layer was separated, washed with saturated NaHCO3 and water, dried, and evaporated. The residue was subjected to column chromatography (silica gel, C6H6) to give 11 as a yellow solid (mp 174-176° C.) in a 74% yield: IR (KBr) 1645, 1655, 1724 (C═O) cm−1; 1H NMR (CDCl3) δ 1.68 (d, J=6.6 Hz, 3H, CHCH3), 2.13 (s, 3H, COCH3), 6.10-6.17 (q, J=6.6 Hz, 1H, CH), 7.53 (s, 1H, H-3), 7.63 (d, J=5.1 Hz, 1H, H-7), 7.68 (d, J=5.1 Hz, 1H, H-6); 13C NMR (CDCl3): δ 21.0 (C-2-COCH3), 22.0 (C-2-CHCH3), 67.4 (C-2-CH), 123.4 (C-3), 126.6 (C-7), 133.6 (C-6), 154.0 (C-2), 174.4×2 169.8 (C-2-C═O), (C-4, C-8); MS m/z 306 (M+); Anal. (C14H10O4S2) C, H.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:31][N:30]=2)[CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[CH:33]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[NH:31][N:30]=4)[CH2:27][CH2:28]3)=[CH:15][CH:16]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1
Reactant: COc1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Reaction time: 0.25 h

Procedure:
4-(6-Methoxy-4-phenylpyridazin-3-yl)benzaldehyde (2-2; 80 mg, 0.27 mmol) was dissolved in dry dimethylformamide (2 mL) and 2-(3-piperidin-4-yl-1H-pyazol-5-yl)pyridine (1-4; 99 mg, 0.43 mmol) and acetic acid (0.14 mL, 2.3 mmol) were added. After stirring for 15 min., sodium triacetoxyborohydride (116 mg, 0.54 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 hours. This reaction mixture was partially evaporated and the residue chromatographed on a silica gel column eluting with a 0-5% methanol/ethyl acetate sat'd with NH4OH. 3-methoxy-5-phenyl-6-(4-{[4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazine (2-3) was obtained as a nearly pure viscous oil. NMR (CDCl3): δ8.60 (1H, d, J=5 Hz), 7.69-7.72 (2H, m), 7.23-7.35 (6H, m), 7.17 (2H, br d, J=7 Hz), 6.98 (1H, s), 6.61 (1H, s), 4.22 (3H, s), 3.52 (2H, s), 2.95 (2H, d, J=12 Hz), 2.72 (1H, m), 2.10 (2H, br t, J=1 Hz), 1.97 (2H, br d, J=12 Hz), 1.81 (2H, br q, J=11).
Reaction SMILES: [OH-].[Na+].Cl.Cl[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.Cl.[SH:13][CH2:14][CH2:15][NH2:16]>C(O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][S:13][CH2:14][CH2:15][NH2:16])[CH:7]=1
Reactant: ClCc1cccnc1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCCSCc1cccnc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
16.8 g of sodium hydroxide was dissolved in 350 ml of ethanol and 17.2 g of 3-chloromethylpyridine hydrochloride and 23.7 g of 2-mercaptoethanamine hydrochloride were added with ice bath cooling. The reaction mixture was allowed to warm to room temperature over 2 hours, was concentrated, diluted with water, and extracted with 3×100 ml of dichloromethane. The combined organic layers were washed with saturated brine, dried over potassium carbonate and concentrated. The residue was distilled to give 12.30 g (70%) of 2-[[(3-pyridyl)methyl]thio]ethanamine, bp 115°-125° C./0.1 mm.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1([CH2:6][O:7][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:5][O:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CO)COC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a mixture of (3-methyl-oxetan-3-yl)-methanol (10.2 g, 0.1 mol) and DMAP (18.3 g, 0.15 mol) in DCM (100 mL) was added 4-methyl-benzenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature for 1 h, then filtered. The filtrate was washed with HCl aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (18 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14](N)=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:19].[K+]>C(O)CC.O>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:19])=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(NCc2ccc(F)cc2)cn1
Reactant: [OH-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1

Procedure:
0.245 g of 5-(p-fluorobenzylamino)-pyridine-2-carboxamide are dissolved in 2.5 ml of warm n-propanol, the solution is combined with 2.5 ml of 20% aqueous potassium hydroxide and the mixture is heated on a steam bath for 16 hours. It is diluted with water and most of the n-propanol removed with a stream of nitrogen. The hot solution is filtered and the pH of the filtrate adjusted to 4 with hydrochloric acid. The precipitate formed is collected, redissolved in aqueous sodium bicarbonate, the solution filtered and reacidified with hydrochloric acid to pH=4. The solid formed is collected and air-dried, to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid melting at 196°-198°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.F.C(F)([F:18])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([F:18])=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(F)F
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Agent: F
Product: O=C(F)Nc1ccc(Cl)cc1C(F)(F)F
Temperature: 24 °C

Procedure:
4-Chloro-2-(trifluoromethyl)phenyl carbamic fluoride was prepared in situ by the reaction of 221 parts of 4-chloro-2-(trifluoromethyl)-isocyanatobenzene and 380 parts of hydrogen fluoride added over a period of about 15 minutes at about 4° C. The reaction mixture was then sealed in a polytetrafluoroethylene reactor, heated to about 24° C. and maintained at about that temperature, with agitation, for about 96 hours. The reactor was then opened to atmospheric pressure and most of the hydrogen fluoride and carbonyl fluoride gases removed. Analysis of the remaining organic product by gas chromatographic techniques, using n-pentadecane as an internal standard, indicated as yield of 55 parts of 4-chloro-2-(trifluoromethyl)benzenamine.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([OH:16])=O)[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:35][NH2:36]>O>[CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([NH:36][O:35][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][O:29]3)=[O:16])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)O)S(C)(=O)=O
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
(2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (100 mg, 0.318 mmol, 1 eq) and CDMT (73.2 mg, 0.413 mmol, 1.3 eq) were charged into a flask. The flask was flushed with nitrogen and then 2-MeTHF (5 mL) added. To this mixture was added N-methylmorpholine (50 uL, 0.445 mmol, 1.4 eq) and the reaction mixture was stirred at RT for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (49 mg, 0.413 mmol, 1.3 eq) was added and the reaction mixture was stirred overnight at RT. Water (25 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL). The organic phases were combined, dried over sodium sulfate, filtered and concentrated to give (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (100 mg, 76% yield) which was used without further purification. LC-MS M+H+414.1.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([S:14][C:15]#N)=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].[CH2:17](Br)C.[I-].[K+]>CO>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH3:17])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCBr
Reactant: COC(=O)c1cc(SC#N)ccc1N
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ccc(N)c(C(=O)O)c1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 31.7 %

Procedure:
To a 500 ml flask fitted with a magnetic stirrer, dropping funnel and thermometer, and containing a solution of 12.7 g (0.192 mol) of 85% potassium hydroxide in 300 ml of methanol was added in portions 10.0 g (0.0481 mol) of methyl 2-amino-5-thiocyanatobenzoate. The solution was cooled to 10° C. and a soltuion of 6.29 g (0.058 mol) ethylbromide in 50 ml of methanol was added over 10 minutes. This was followed by the addition of 8.0 g (0.048 mol) potassium iodide. After 2.5 hours, the reaction mixture was evaporated to a semi-solid under reduced pressure and treated with 300 ml of water. The aqueous solution was extracted with chloroform, and the organic layer dried over magnesium sulfate. The solution was filtered and evaporated to give 7.5 g (79%) of crude product. This material was recrystallized from hexane to give 3.01 g (32%) of the title compound, m.p. 97°-100° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].CC(C)=O.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([CH3:22])=[CH:16][C:17](=[O:21])[O:18]2)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.[I-].[K+]>[CH2:2]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([CH3:22])=[CH:16][C:17](=[O:21])[O:18]2)=[CH:13][CH:12]=1)[C:3]([CH3:4])=[O:5]
Reactant: CC(=O)CCl
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)COc1ccc2c(C)cc(=O)oc2c1
Yield: 97.5 %

Procedure:
A mixture of chloroacetone (26.23 mL, 30.48 g, 0.329 mol), potassium iodide (1.0 g, 6 mmol), and reagent grade acetone (dried over K2CO3, ca. 400 mL) was allowed to stand for 151/2 hours. 7-Hydroxy-4-methylcoumarin (50.0 g, 0.284 mol), anhyd. K2CO3 (45.50 g, 0.321 mol), and dry reagent grade acetone (1 L) were added and the mixture was refluxed for 24 hours with overhead stirring. The hot mixture was filtered and the precipitate was washed with acetone. The washes and the filtrate were combined and evaporated in vacuo to obtain a yellow solid, which dissolved in CHCl3 (1.3 L). The CHCl3 solution was extracted once with 5% aq. NaOH (500 mL), washed with two portions (500 mL) of water, dried (MgSO4), and evaporated in vacuo to obtain 7-acetonyloxy-4-methylcoumarin (64.30 g, 97.5%), mp 146.0°-148.0° C. Recrystallization of 61.82 g from 95% ethanol gave a purer product (53.91 g, 87% recovery, 85% yield), mp 150.1°-151.2° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a brown solid (352 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.BrC1C=CC=CC=1[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:33]>CC#N>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH:13]([CH2:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:14]2)=[CH:35][CH:36]=1
Reactant: O=C(Cc1ccccc1Br)c1ccc(F)cc1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (75 mg, 0.28 mmol) in MeCN (5 mL) was treated with Et3N (97 μL, 0.7 mmol) and 2-bromo-4′-fluorophenylacetophenone (68 mg, 0.31 mmol) and stirred for 30 min at room temperature. The reaction was evaporated and the residue dissolved in DCM and purified using silica chromatography. The column was eluted with 1% MeOH/DCM to give the title compound as a white solid (70 mg, 68%). 1H NMR (500 MHz, CDCl3) δ 2.94–2.99 (1H, m), 3.10 (2H, t, J=7.4 Hz), 3.42 (2H, d, J=7.4 Hz), 3.62 (2H, t, J=7.4 Hz), 3.87 (2H, s), 7.12 (2H, t, J=8.8 Hz), 7.25 (2H, t, J=8.6 Hz), 7.90–7.94 (4H, m). m/z (ES+) 366 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:13]OC1CCCCO1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:26][CH2:13][CH2:12][CH:11]([C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: COC(=O)C(CCOC1CCCCO1)c1ccc2ccccc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CCBr)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
The product of step (a) (2.0 g, 6.1 mmol) and carbon tetrabromide (2.83 g, 8.5 mmol) were dissolved in dichloromethane (30 ml) and cooled to 0° C. under nitrogen. Triphenylphosphine (4.48 g, 17.1 mmol) was added portionwise turning the reaction mixture deep yellow. After stirring at room temperature for 18 hours the reaction mixture was concentrated under reduced pressure. The oil was purified by flash chromatography on silica gel eluting with 1:1 dichloromethane:hexane to give 1-bromo-3-(methoxycarbonyl)-3-(2-naphthyl)propane as a white solid (0.56 g, 30%).