Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCO>[C:11]1([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A mixture of 4,4,4-trifluoro-3-oxobutanenitrile (2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quenched with water, basified with saturated NaHCO3 solution, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:36]([NH:39][NH2:40])(=[O:38])[CH3:37]>O1CCCC1>[C:36]([NH:39][NH:40][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])(=[O:38])[CH3:37]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of the carboxylic acid (6b, 2.37 g, 8.57 mmol) of Example 9 or 16 in tetrahydrofuran (50 mL) were added triethylamine (1.39 mL) and isobutyl chloroformate (1.32 mL) under ice-cooling, followed by agitating at 0° C. for 20 minutes. To the reaction solution was added acetohydrazide (807 mg) at 0° C., stirred at room temperature for 40 minutes and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to afford 2.61 g of the title compound (yield 92%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[C:6]=1I.C([Li])CCC>C1COCC1.CCCCCC>[I:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)[CH:6]=1
Reactant: Cc1nc(I)c(I)n1-c1cnn(C)c(=O)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(I)cn1-c1cnn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A solution of 240 mg (0.543 mmol) 5-(4,5-diiodo-2-methyl-imidazol-1-yl)-2-methyl-2H-pyridazin-3-one in 17 ml of dry THF was cooled to −78° C. and 0.41 ml of a 1.6M solution of n-butyllithium (0.65 mmol) in hexane was added. The mixture was stirred for 5 min., quenched by addition of 0.5 ml of methanol and stirred for an additional 10 min at −78° C. Then 2 ml of saturated ammonium chloride solution was added and the mixture was allowed to warm up to room temperature. After standard workup with ethyl acetate/water, the crude material was purified by flash chromatography on silicagel using a 90:10 mixture of ethyl acetate/heptane as eluant to yield 53 mg (0.168 mmol, 31%) of the title compound as a light yellow solid, MS: m/e=316.9 (M+H+).
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:18])[CH2:13][CH2:14][CH:15]=[CH:16][CH3:17])[O:9][C:8]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N=C=NCCCN(C)C)C.[CH:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32]>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH:31]([NH:33][CH2:34][C:35]([O:18][C@H:12]([CH2:13][CH2:14][CH:15]=[CH:16][CH3:17])[CH2:11][C@H:10]1[C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:19])[O:9]1)=[O:36])=[O:32]
Reactant: CC=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: O=CNCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: CC=CCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CNC=O
Yield: 57.1 %

Procedure:
Prepared according to representative procedure described in Example 48 above (i.e., acylation) using hydroxy β-lactone 13k (15.6 mg, 0.058 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (14.4 mg, 0.075 mmol), 4-dimethylaminopyridine (8.7 mg, 0.070 mmol), 0.5 mL of xylene were azeotroped in vacuo for 1.0 h. The residue was then dissolved in CH2Cl2 (1.5 mL) and N-formyl glycine (9.0 mg, 0.087 mmol) was added. After twelve hours resulting mixture was purified by chromatography (SiO2, gradient 10-40% EtOAc:hexanes) to afford β-lactone 17g (11.7 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:30])([F:29])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][C:25](=O)[CH2:24][C:23](=[O:28])[CH2:22]2)=[CH:17][CH:16]=1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:25]1[CH2:26][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:30])([F:29])[F:13])=[CH:16][CH:17]=2)[CH2:22][C:23](=[O:28])[CH:24]=1)([O:6][CH3:7])=[O:5]
Reactant: O=C1CC(=O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: COC(=O)c1cccc(N)c1Br
Product: COC(=O)c1cccc(NC2=CC(=O)CC(c3ccc(C(F)(F)F)cc3)C2)c1Br
Temperature: 150 °C
Yield: 67.4 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (10.2 g, 44.3 mM) and 5-(4-trifluoromethylphenyl)-1,3-cyclohexanedione (1.77 g, 6.93 mM) was heated at 150° C. under a stream of nitrogen for 20 minutes. The resultant solid was triturated with 4:1 EtOAc/Et2O to afford 2.18 g (74%) of 3-(3-carbomethoxy-2-bromoanilino)-5-(4-trifluoromethylphenyl)-cyclohex-2-en-1-one. 1H NMR (DMSO-d6) δ 8.9 (s, 1H), 7.75-7.5 (m, 7H), 3.9 (s, 3H), 3.5 (m, 1H), 2.9 (dd, J=14 and 9 Hz, 1H), 2.7 (dd, J=14 and 4 Hz, 1H), 2.55 (dd, J=14 and 9 Hz, 1H), 2.35 (dd, J=14 and 4 Hz, 1H). MS (ES) m/e 368, 370.
Reaction SMILES: [CH:1](=O)[CH3:2].[ClH:4].Cl.Cl.[CH3:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[NH:19])=[NH:16])=[CH:11][CH:10]=1>C(O)C>[ClH:4].[CH2:21]([NH:20][CH:18]1[N:19]=[C:1]([CH3:2])[N:16]=[C:15]([NH:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:33][CH:32]=2)[NH:17]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(OC)cc1
Reactant: CC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCNC1N=C(C)N=C(NCc2ccc(OC)cc2)N1

Procedure:
Under ice-cooling, 100 ml of ethanol, 5 ml (89.2 mmol) of acetaldehyde and 0.4 ml of concentrated hydrochloric acid were added to 4.0 g (8.9 mmol) of N1-(4-methoxybenzyl)-N5-undecyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and dissolved in 70% aqueous acetonitrile. The solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 1.4 g of a colorless resinous solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:45])(=[O:44])[NH:39]C(C)(C)C)=[CH:28][C:27]=2[F:46])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:44])(=[O:45])[NH2:39])=[CH:28][C:27]=2[F:46])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(C)(C)C)cc3F)c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A solution of 32 mg (0.048 mmol) of 5-n-butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step F) in 0.5 mL of trifluoroacetic acid (TFA) containing 2 drops of anisole was stirred overnight at room temperature. The excess TFA was removed by evaporation under a gentle stream of N2. The residue was reconcentrated from toluene twice in vacuo and flash chromatographed over 15 cc of silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) to give 20 mg (69%) of the title compound as a white solid, mp 108°-110° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 614 (M+1)+.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:31](=[O:33])[NH2:32])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>ClCCl>[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:31]([NH2:32])=[O:33])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:40][CH2:39]1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F
Reactant: CN(C)CCN1CCNCC1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4CCN(CCN(C)C)CC4)cc32)sc1C(N)=O)c1ccccc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
136 mg of crude (1-{5-carbamoyl-4-[(1R)-1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate (example 101, step 1) are dissolved in 5 ml dichloromethane. Under N2 atmosphere N,N-dimethyl-2-piperazin-1-ylethanamine (218 mg) is added. The reaction mixture is stirred at 40° C. for 2 hours and 2 hours at room temperature. It is then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl.O=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18](OC)=[O:19]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:19])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Product: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 35.8 %

Procedure:
Prepared by the method described for Example 1 from 3-methoxyphenol (16 g, 0.126 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (25 g, 0.129 moles). Recrystallization from ethanol gave the product (10.43 g), mp 179°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperidine-1-carboxylate (0.0483 g, 0.119 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0174 g, 0.119 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate), and the resulting crude product was purified again by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperidine-1-carboxylate (0.0454 g, 72%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.C1COCC1.[O:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][O:32]2)=[O:38])=[C:4]([F:26])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)[C@H]1CCCO1
Yield: 13.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-70, 0.090 g, 0.233 mmol), THF:DMF (5 mL:1 mL), (R)-(−)-tetrahydrofuran-2-carboxylic acid (0.040 g, 0.349 mmol), TBTU (0.224 g, 0.699 mmol), and TEA (0.5 mL). The obtained crude was purified with column chromatography using basic alumina as stationary phase and 2% ammonia in 10.0% MeOH:DCM solution as mobile phase to afford 0.015 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.78-1.91 (m, 2H), 2.09-2.15 (m, 1H), 3.74 (m, 1H), 3.88-3.94 (m, 1H), 4.28 (m, 1H), 4.43 (m, 2H), 7.65 (m, 2H), 7.86 (d, J=8.72 Hz, 2H), 8.18 (d, J=8.52 Hz, 2H), 8.45 (d, J=16.0 Hz, 1H), 12.71 (s, 1H).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1>>[O:18]=[C:19]1[C:27]2([C:31]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=3[O:29][CH2:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: BrCc1ccccn1
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: Br
Agent: BrCC1CCCCO1
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (89%) as a colorless solid: mp 151-153° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=3.9 Hz, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.34-6.84 (m, 9H), 5.19 (d, J=15.8 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.97 (d, J=15.8 Hz, 1H), 4.79 (d, J=9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.3, 160.7, 155.1, 149.7, 142.3, 137.1, 134.8, 131.2, 129.5, 125.8, 124.6, 123.8, 122.9, 121.8, 118.5, 113.8, 113.3, 109.9, 80.21, 77.5, 57.9, 46.1; MS (ES+) m/z 353.9 (M+1).
Reaction SMILES: [S:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[C:2]#N.[BH4-].[Na+].CS(OC[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O>CN(C)C=O>[CH2:2]([S:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCc1ccccc1
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
To a solution of 19.5 g (0.1 mol) 4-thiocyano-2-nitroaniline in 130 ml dimethylformamide is added 3.78 g (0.1 mol) sodium borohydride, all at once. The mixture is stirred for one-half hour, then 15.2 g (0.1 mol) benzyl methanesulfonate in 70 ml dimethylformamide is added. The solution is stirred at 30° for 3 hours, cooled and partitioned between water and dichloromethane. The layers are separated and the aqueous phase reextracted with dichloromethane. The organic phases are combined, washed with aqueous K2CO3, water and saturated NaCl, dried, filtered and stripped to yield 4-(benzyl)sulfenyl-2-nitroaniline.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:17]=2[O:16][CH3:15])[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: COc1cccc(CN)c1OC
Solvent: CCN(CC)CC
Product: COc1cccc(CNc2nc(Cl)nc3c2ncn3C(C)C)c1OC

Procedure:
2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 for preparation), 2,3-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: CCO
Product: CCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and ethanol. Light brown solid. MS (m/e): 208.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH2:1]([C:3]([N:12]=[C:13]=[O:14])([CH2:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH3:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]([NH:20][CH3:21])[CH3:19]>>[CH3:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]([N:20]([CH3:21])[C:13]([NH:12][C:3]([CH2:10][CH3:11])([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:14])[CH3:19]
Reactant: CCC(CC)(N=C=O)c1ccccc1
Reactant: CNC(C)c1ccccc1C
Product: CCC(CC)(NC(=O)N(C)C(C)c1ccccc1C)c1ccccc1
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A mixture consisting of 9.5 g of α,α-diethylbenzylisocyanate and 7.5 g of N-(2-methyl-α-methylbenzyl)-N-methylamine was allowed to stand for 3 hours at room temperature. The white deposit formed was then filtered off. Washing with n-hexane and recrystallization from ethanol gave 15.9 g of the product, mp 93.0°-94.0° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOCC>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: O=C1CCc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C1CCc2cc(-n3cccn3)ccc21
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Combine 5-fluoro-indan-1-one (1.02 g, 6.79 mmol), pyrazole (0.46 g, 6.79 mmol), and potassium carbonate (1.03 g, 7.47 mmol, 1.10 equivalents) in dimethyl sulfoxide (5 ml) in a sealed tube and heat to 100° C. for 48 hours. Cool to room temperature, dilute with ether, wash with water (2×), dry over anhydrous sodium sulfate, and concentrate to obtain the title compound as a brown solid (0.98 g, 73%). LC-MS m/z 199.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:14][CH:15]([C:21]([CH3:23])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([NH2:1])[C:3]=1[C:4]#[N:5])([CH3:14])[C:21](=[O:22])[CH3:23])[CH3:20]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(N)c1C#N
Reaction time: 24 h
Yield: 45.5 %

Procedure:
To a solution of 2-amino-6-chloro-3-nitrobenzonitrile (1.97 g, 10 mmol) and ethyl 2-methylacetoacetate (3.6 g, 25 mmol) in DMF (10 mL) was added finely powdered K2CO3, and the mixture stirred vigorously for 24 h. The deep red mixture was diluted with EtOAc and washed in turn with 2 M HCl, water and brine. The residue after evaporation was purified by flash chromatography in hexane/EtOAc 3:1 to yield 2-(3-amino-2-cyano-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (1.39 g, 46%), MS (NH3 CI) 323 (M+NH4+), 293 (M+NH4−NO+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[N:33]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)(=[O:41])=[O:40])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)N1CCOCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)N1CCOCC1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}morpholine-4-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and morpholine-4-sulfonyl chloride following General Procedure U.
Reaction SMILES: [OH:1][C@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:19]([CH3:27])([CH2:20][CH2:21][C:22]=32)[C@@H:11]([C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH:9]=4)[C:3]1([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36](Cl)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:16][C:15](=[O:17])[CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:19]2([CH3:27])[C:8]([C:7]3[CH2:6][CH2:5][C@@H:4]4[C@:23]([C:22]=3[CH2:21][CH2:20]2)([CH3:26])[CH2:24][CH2:25][C@H:2]([OH:1])[C:3]4([CH3:28])[CH3:29])=[CH:9][CH2:10]1)[CH3:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: ClCc1ccccc1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CCC(=O)OCc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3β-Hydroxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid (100 mg) is suspended in 5 ml of dry DMF. 811 mg of cesium carbonate and 0.29 ml of benzyl chloride is added and the mixture is stirred at 50° C. overnight. After aqueous work-up, column chromatography and crystallisation from acetone/water 55 mg of the title compound is obtained. Melting point: 118-119° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[C:16]([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:25]3)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)C3CC3)cc2[N+](=O)[O-])C1
Yield: 96 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrophenyl cyclopropyl ketone (1.0 eq), 3-(N-Boc-amino)piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-(cyclopropanecarbonyl)-2-nitrophenyl)piperidin-3-ylcarbamate (96%). LCMS (m/z): 390.1 (MH+); LC Rt=3.28 min.