Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:28][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(-n2ccnc2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 78 mg of 4-(1H-imidazol-1-yl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-imidazol-1-yl)benzamide. MS (Q1) 375.3 (M)+.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCCCCCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Reaction time: 2 h
Yield: 68 %

Procedure:
To sodium metal (1.32 g, 0.0573 mol) dissolved in dry ethanol (150 ml) under argon at room temperature was added diethyl malonate (14.13 g, 0.088 mol) over a period of 10 minutes and the solution left for 2 hours. B1 (10.0 g, 0.044 mol) was then added dropwise over 2 hours and this solution heated at reflux overnight. Excess salts were quenched by the addition of 50 ml of water and the total solvent volume reduced to 50-100 ml. Diethyl ether (100 ml) and water (50 ml) were added and the aqueous layer extracted 3 times with diethyl ether. The organic fractions were combined, dried (K2CO3), and the solvent removed to yield the crude product as a yellow oil. Distillation of the oil (0.5 mBar, 220° C.) gave the title compound (10.52 9, 68%) as a colourless viscous oil. δH (CDCl3) 1.32 (6H, t, Me), 1.43 (6H, br s, (CH2)3CH2CH), 1.69 (2H, p, CH2CH2O), 1.99 (2H, q, CH2CH), 3.39 (1H, t, CH), 3.53 (2H, t, CH2OCH2Ph), 4.25, 4.28 (4H, 2×q, OCH2Me), 4.57 (2H, s, CH2Ph), 7.3-7.4 (5H, m, Ph). δC (CDCl3) 13.9 (2C, Me), 25.7 (1C, CH2(CH2)2CH), 27.1 (1C, CH2(CH2)2O), 28.5 (1C, CH2CH2CH), 28.9 (1C, CH2CH2O), 29.5 (1C, CH2CH), 51.8 (CHCO2Et), 61.0 (2C, OCH2Me), 70.1, 72.7 (2C, CH2OCH2), 127.3 (1C, CH(CH)2C), 127.4 (2C, CHC), 128.1 (2C, CHCHC), 138.5 (1C, CCH2O), 169.3 (2C, CO2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[O:47][C:46]([S:48]([N:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)(=[O:50])=[O:49])=[CH:45][C:44]=2[CH:57]=1>CN(C)C=O>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[O:47][C:46]([S:48]([N:51]3[CH2:56][CH2:55][N:54]([C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[CH:15][CH:14]=4)[CH2:53][CH2:52]3)(=[O:49])=[O:50])=[CH:45][C:44]=2[CH:57]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2o1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CC1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A stirred suspension of 4-(4-pyridyl)benzoic acid (133 mg, 0.67 mmol) in dimethylformamide (5 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (108 mg, 0.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg, 0.8 mmol) and 1-(5-chlorobenzofuran-2-ylsulphonyl) piperazine (201 mg,0.67 mmol). After stirring overnight the solvent was removed in vacuo and the residue chromatographed (Merck Art 9385 silica, eluting with dichloromethane containing 2% v/v of methanol) to yield 1-(5-chlorobenzofuran-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine as a colourless solid (40 mg), 1H NMR (CDCl3) δ=3.2-3.4 ppm (broad s, 4H), δ=3.6-4.0 ppm (broad s, 4H), δ=7.35 ppm (s, 1H), δ=7.5 ppm (m, 6H), δ=7.7 ppm (m, 3H), δ=8.7 ppm (d, 2H), MS (M+H)+ 482/484.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[O:7])[CH3:6].[BH4-].[Na+]>CO>[CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]([OH:7])[CH3:6]
Reactant: CC(=O)C(CC(C)C)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(c1ccccc1)C(C)O
Reaction time: 1.5 h

Procedure:
A solution of 66 mg (0.345 mmol) of 5-methyl-3-phenyl-2-hexanone in 1 mL MeOH was treated with 16 mg sodium borohydride. After 1.5 h, the reaction was quenched with 1.2 N HCl and concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried and concentrated to yield the crude title compound which was used without purification. 1H NMR: (500 MHz, CDCl3): δ 0.88 (2d, 6H), 1.0-1.8 (m, 4H), 1.2 (d, 3H), 2.64 (m, 1H), 3.9 (m, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:23](=[CH:24][CH:25]=2)[C:22]2[O:21][N:20]=[C:19]([C:26]([O:28]C)=[O:27])[C:18]=2[CH2:17][CH2:16]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:23](=[CH:24][CH:25]=2)[C:22]2[O:21][N:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]=2[CH2:17][CH2:16]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1noc2c1CCc1cc(CN3CC(C(=O)OC(C)(C)C)C3)ccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc3c(c2)CCc2c(C(=O)O)noc2-3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
A mixture of methyl 7-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45D, 95 mg, 0.238 mmol) and lithium hydroxide monohydrate (12.01 mg, 0.286 mmol) in THF (3 mL) and water (1.500 mL) was allowed to stir at room temperature overnight. The THF was evaporated and the residue diluted with 5 ml of water. The pH was adjusted to 5-6 and extracted with ethyl acetate six times. The organic layers were combined, dried over sodium sulfate and concentrated to afford 110 mg of product (HPLC purity 75-80%). The compound had an HPLC ret. time=0.67/2.0 min. (condition E); MS:(M+H)=385.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14](O)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)C>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1CO
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a solution of 5-(4-chlorophenyl)-2-methylfuran-3-carboxylic acid (0.104 g, 0.44 mmol) in THF (2 mL) and MeOH (2 mL) was added TMSCHN2 (2.0 M in Et2O, 0.250 mL). The reaction mixture was stirred for 18 hours at which time it was concentrated in vacuo. The residue was dissolved in 1 ml of THF at 0° C., and a solution of LAH (1.0 M in THF, 0.8 mL) was added. After addition, the reaction was stirred at room temperature for 2 hours, and then water (0.24 mL), 15% aqueous NaOH (0.24 mL), and water (0.72 mL) were added sequentially to the reaction. After 30 minutes, the reaction mixture was filtered through celite, and the filtrate was concentrated to give 53.1 (0.056 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.63 (m, 2 H), 7.31-7.40 (m, 2 H), 6.64 (s, 1 H), 4.52 (s, 2 H), 2.37 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=2[N:20]=1)([C:7]1[C:15]([O:16]C)=[CH:14][C:13]([CH3:18])=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([F:6])([F:5])[F:4].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=2[N:20]=1)([C:7]1[C:15]([OH:16])=[CH:14][C:13]([CH3:18])=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([F:6])([F:5])[F:4]
Reactant: COc1cc(C)c2[nH]ccc2c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(C(N)(c2nc3cc(C#N)ccc3[nH]2)C(F)(F)F)c2cc[nH]c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (−)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 36-E-b) (63 mg, 0.158 mmol) in methylene chloride (Volume: 1.6 mL) at 0° C. was added 1 M BBr3 in DCM (315 μl, 0.315 mmol). The reaction was stirred in ice bath for 5 minutes and then the suspension was allowed to stir at room temperature for 2 hours. The reaction was poured into ice water, treated with saturated a solution of sodium bicarbonate, and then diluted with EtOAc and the EtOAc layer was removed, dried, concentrated and absorbed onto silica to purify via FCC (0-5% MeOH containing 10% ammonium hydroxide:dcm) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.55-12.76 (m, 1H) 11.01-11.28 (m, 1H) 10.82 (br. s., 1H) 8.35 (s, 1H) 7.83-8.06 (m, 1H) 7.46-7.65 (m, 2H) 6.88 (t, J=2.91 Hz, 1H) 6.50 (s, 1H) 4.84 (br. s., 1H) 2.27-2.43 (m, 3H). MS (ESI+) m/z 386.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:37][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Reaction time: 24 h

Procedure:
2-Methyl-4-nitro-1-pentafluoroethyl-benzene (2.55 g) was dissolved in CCl4 (30 ml) and AIBN (164 mg) and NBS (1.96 g) were added. The reaction was heated to reflux and stirred for 24 h. The mix was diluted with CH2Cl2, washed with sat'd NaHCO3, dried over MgSO4 and concentrated to give the compound as an oil which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1.[CH3:27][NH:28][CH3:29].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[CH3:27][N:28]([CH3:29])[C:14]([C:12]1[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=[C:8]([Cl:7])[N:13]=1)=[O:16]
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Oxalyl chloride (0.38 mL, 4.5 mmol) and N,N-dimethylformamide (0.03 mL) were added to a suspension of 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid (303 mg, 1.0 mmol) in dichloromethane (20 mL). The mixture was stirred at 20° C. for 3 h and then evaporated under reduced pressure. The residue was dissolved in dichloro-methane (25 mL) and the solution was stirred together with 60% aqueous dimethylamine (1.2 mL, 13.3 mmol) and saturated aqueous sodium hydrogencarbonate solution (8 mL) for 1 h at 20° C. The mixture was diluted with dichloromethane (25 mL), and the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-40% ethyl acetate as eluent to give the title compound (215 mg, 65%) as a white solid. MS ISP (m/e): 330.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.24 (d, 2H), 7.99 (s, 1H), 7.80 d, 2H), 3.17 (s, 6H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[N:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)CCC>COCCOC>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:4]2[S:3][C:2]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[N:6][N:5]=2)=[CH:9][CH:10]=1)([CH3:17])[CH3:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)Oc1ccc(Oc2nnc(Br)s2)cc1
Solvent: COCCOC
Product: CC(C)Oc1ccc(Oc2nnc(-c3cccs3)s2)cc1
Temperature: 25 °C
Yield: 195.5 %

Procedure:
A solution of Example 24C (0.58 g, 1835 mmol) and 2-tributylstannylthiophene (0.816 ml, 2.57 mmol) in DME (15 mL) was degassed by bubbling nitrogen into the reaction mixture via a 20-gauge needle for 10 minutes. PdCl2(PPh3)2 was added and the reaction was heated at reflux under a nitrogen atmosphere for 20 hours. The reaction was cooled to 25° C. and concentrated under reduced pressure on a rotary evaporator to provide 1.6 g of a golden oil. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 15% ethyl acetate in hexanes to provide 0.51 g (88%) of the title compound as a pale purple oil which crystallized on standing, 1H NMR (300 MHz, DMSO-d6) δ ppm 7.79 (d, J=5.15 Hz, 1H) 7.66 (d, J=3.68 Hz, 1H) 7.40 (d, J=9.19 Hz, 2H) 7.18 (dd, J=5.15, 3.68 Hz, 1H) 7.03 (d, J=9.19 Hz, 2H) 4.64 (heptet, J=5.88 Hz, 1H) 1.28 (d, J=5.88 Hz, 6H); MS (DCI) m/z 319 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[NH:17][C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:25]N(C)C=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]([CH3:22])[CH:18]([CH3:23])[N:17]([CH3:25])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C
Reactant: CN(C)C=O
Product: CC(C)OC(=O)c1cc(N2C(=O)C(C)C(C)N(C)C2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,5-dihydro-3,4,5-trimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 119°-120° C.,
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([S:23]([N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[O:42][CH3:43])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:22][C:21]1[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][C@@H:9]([OH:8])[CH2:10][C@@H:11]2[C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)=[CH:17][C:18]([F:44])=[C:19]([S:23]([N:26]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:20]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 86.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the 4-{[(1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (90.0 mg, 0.120 mmol) prepared in Example 161b, tetrabutyl ammonium fluoride (1.0 M solution in THF; 0.241 mL, 0.241 mmol) and THF (5.0 mL), to yield the title compound (65.3 mg, 86%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:12][CH:11]2[C:6]([C:22]3[S:23][C:24]([F:27])=[CH:25][CH:26]=3)([N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9][CH2:10]2)[CH2:5]1)[CH:2]=[CH2:3]>CO.C(Cl)(Cl)Cl>[F:27][C:24]1[S:23][C:22]([C@:6]23[CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:12][C@H:11]2[CH2:10][S:9][C:8]([NH:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:7]3)=[CH:26][CH:25]=1
Reactant: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2ccc(F)s2)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CCN1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)s2)C1

Procedure:
Racemic N-[6-allyl-7a-(5-fluoro-2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (4.71 g, 11.73 mmol) is dissolved in 1:1 MeOH/CHCl3 (20 mg/mL) and separated into its constituent enantiomers by chiral HPLC (Column: Chiralcel OD 8×32 cm (20 μM); mobile phase: 60:40 IPA/heptane; flow rate 385 mL/min at UV 290 nm; 0.320 g/injection). Analysis of the second eluting isomer (Column: Chiralcel OD-H 4.6×150 mm; mobile phase: 60:40 IPA/heptane; flow rate 0.6 mL/min at UV 290 nm) gave the title compound, Rt=8.2 minutes (2.01 g, 43%, 96.1% ee). ES/MS (m/e): 402.0 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[CH2:18]([C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1)[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:22][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH2:18][CH3:19])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CCC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with sodium hydride (0.581 g, 50-60%) in dry DMF (10 mL) at 0° C. and to it was added 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (0.8 g). The reaction mixture was stirred at RT for 30 min., and then to this was added 4-(2-ethyloxiran-2-yl)pyridine (0.758 g) dissolved in DMF (2 mL), stirred at RT for 12 h. The reaction mixture was diluted with ice-water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was triturated with diethyl ether to obtain the desired compound. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.45 (d, 2H), 7.40 (m, 4H), 7.0 (d, 1H), 4.38 (m, 1H), 4.22 (m, 1H), 3.60 (m, 2H), 3.35 (m, 2H), 3.10 (m, 2H), 2.90 (s, 3H), 2.10 (m, 2H), 0.6 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[CH3:29][C@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH3:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([N:3]3[CH2:4][CH2:5][C:6]4([CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)[C:2]3=[O:1])=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Product: C[C@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 9 by condensing cis-methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and (S)-2-methylpyrrolidine.
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:9].[CH2:10]([OH:12])[CH3:11]>>[ClH:9].[CH:1]1([C:7](=[NH:8])[O:12][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1CCCCC1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Cyclohexanecarbonitrile (1.0 g, 9.2 mmol) was dissolved in anhydrous ethanol under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 100%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (m, 1H), 11.03 (m, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.62 (m, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.70-1.65 (m, 3H), 1.40-1.38 (m, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.23-1.19 (m, 3H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C@H:10]([NH2:12])[CH3:11])[CH:6]=[N:5]1.CC1N(C[C:20]([F:23])([F:22])[F:21])N=CC=1C(=O)C>>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:4]([CH2:3][C:20]([F:23])([F:22])[F:21])[N:5]=[CH:6][C:7]=1[CH:10]([NH2:12])[CH3:11]
Reactant: CC(=O)c1cnn(CC(F)(F)F)c1C
Reactant: Cc1c([C@@H](C)N)cnn1C
Agent: Cl
Product: Cc1c(C(C)N)cnn1CC(F)(F)F
Yield: 99 %

Procedure:
The title compound was prepared in >99% yield by the same process as described for (R)-1-(1,5-dimethyl-1H-pyrazol-4-yl)ethanamine dihydrochloride (Amine 2) using 1-(5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ethanone (Step A6A) as a starting material. 1H NMR (300 MHz, DMSO-d6) δ 1.49 (3H, d, J=6.0 Hz), 2.32 (3H, s), 4.29-4.33 (1H, m), 5.07 (1H, d, J=9.0 Hz), 5.13 (1H, d, J=9.0 Hz), 7.72 (1H, s), 8.34 (3H, brs).
Reaction SMILES: [C:1]1(C)[CH:6]=C[C:4]([NH:7][C:8]2C=CC=C[C:9]=2C=O)=[CH:3][CH:2]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([CH2:24][C:25](=O)[CH3:26])=[O:23].N1CCCCC1>C(O)C>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([C:24]1[C:8]([CH3:9])=[N:7][C:4]2[C:26]([CH:25]=1)=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:23]
Reactant: CC(=O)CC(=O)c1ccco1
Reactant: Cc1ccc(Nc2ccccc2C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1nc2ccccc2cc1C(=O)c1ccco1
Yield: 77 %

Procedure:
A solution of 410 mg (1.95 mmol) N-(p-tolyl)-o-aminobenzaldehyde 326 mg (2.15 mmol), (2-furoyl)acetone and 50 mg piperidine in 4 ml 95% ethanol was heated overnight under reflux. Removal of he volatile materials left a black, gummy oil which was taken up in dichloromethane and, after being washed with 3M NaOH, brine, and dried (MgSO4), purified by flash chromatography [eluent, 3:2 pentane-diethyl ether (3:2)] yielding 355 mg (1.50 mmol, 77%) product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([O:23]C(C)(C)C)=[O:22])[S:17][CH:18]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]3[N:15]=[C:16]([S:19][C:20]([CH3:29])([CH3:28])[C:21]([OH:23])=[O:22])[S:17][CH:18]=3)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2ccc(F)cc2)ccc1OCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
4-(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethoxy)-4′-fluoro-biphenyl-3-carboxylic acid methyl ester (250 mg) obtained in Example 92-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (175 mg) as a colorless oil.
Reaction SMILES: O.[ClH:2].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10]C(C)=O)[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[ClH:2].[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(-c2ccccc2)c(C)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)ccc1-c1ccccc1

Procedure:
300 g of water and 296 g of HCl (37%) are added to the 2-methyl-4-acetaminobiphenyl prepared as described in Example 1. Any chlorobenzene still present is distilled off azeotropically, and the mixture is subsequently refluxed until HPLC monitoring indicates complete conversion (about 4 hours). The suspension obtained can be reacted further without further purification and without removal of the acetic acid formed as coproduct in the cleavage. The yield is (calculated from HPLC percentages by area) 99%.