Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[S-:13][C:14]#[N:15].[Na+].BrBr.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:14]([NH2:15])[S:13][C:7]=2[CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(N)sc2c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of ethyl-4-aminobenzoate (35 g, 212 mmol) in glacial acetic acid (300 mL) was added to a stirred solution of sodium thiocyanate (69 g, 848 mmol) in acetic acid (150 mL). The mixture was cooled in an ice-water bath and a solution of bromine (12 mL, 233 mmol) in acetic acid (60 mL) was added dropwise via an addition funnel. The reaction mixture was stirred at 0° C. to RT for 4 h and then poured into water (1.5 L). Saturated sodium carbonate solution was added to neutralize the solution. Precipitated solid was filtered, washed with water and EtOAc, and dried in vacuo to obtain the title compound of this step (31.65 g, 67.2% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C([O-])(=O)C.[Cs+].[CH3:28][NH2:29].CO.O>CN(C)C=O.[Cu](I)I>[CH3:28][NH:29][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(Br)cc12
Agent: I[Cu]I
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
30 mg (0.08 mmol) of the 7-bromo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one prepared in Step A, 18.6 mg (0.098 mmol) of copper iodide (I), and 39.1 mg (0.204 mmol) of cesium acetate were suspended in 0.5 ml of dry dimethylformamide. Thereafter, 200 μl of a 40% methylamine-methanol solution was added to the suspension, and the obtained mixture was then stirred at 100° C. overnight. Thereafter, water was added to the reaction solution, and the mixture was then extracted with methylene chloride. The extract was washed with a saturated saline solution, and was then dried over anhydrous magnesium sulfate. The extract was concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1), so as to obtain 15.4 mg (61%) of 7-methylamino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:37]([C:39]1[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=1)=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.ClCCl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:6][N:7]([C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[N:18]([CH2:37][C:39]2[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(Cc3ccc(C(=O)O)s3)c3cc4c(cc32)COC4)n1

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 73, Step 7) (0.16 mmol) in dichloroethane (5 mL), add 5-formyl-thiophene-2-carboxylic acid (0.63 mmol) followed by acetic acid (cat.). Add NaB(OAc)3H (0.78 mmol) and stir the mixture at room temperature for 14 h. Dilute the reaction with dichloromethane (10 mL) and quench with water (5 mL). Separate the organics and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over Na2SO4, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with MeOH/DCM (1-5%) to provide the title compound as a colorless foam. MS (ES+): 651 (M−H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:19][CH:18]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCOc1ccc(I)cc1

Procedure:
Quantities: anhydrous potassium carbonate (30 g, 0.22 mol), 1-bromooctane (11.7 g, 0.06 mol) and 4-iodophenol (11.0 g, 0.05 mol). The experimental procedure was as described in Example 119.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:2]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[Br:22][CH2:14][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[O:7][C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H](C)Oc1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)Oc1cccc(CBr)c1
Temperature: 80 °C

Procedure:
To a 250 mL round-bottom flask was (S)-methyl 2-(m-tolyloxy)propanoate (2.0 g, 10.3 mmol, 1 equiv), NBS (1.83 g, 10.3 mmol, 1 equiv), AIBN (169 mg, 1.03 mmol, 0.1 equiv) and CCl4 (100 mL). The reaction mixture was refluxed for 16 h at 80° C. The completion of the reaction was monitored by analytical HPLC. The reaction mixture was allowed to cool to room temperature. The crude mixture was dissolved in AcOEt (100 mL) and washed with a 0.5N HCl aqueous solution (×2), a saturated NaHCO3 solution (×2) and brine, dried over Na2SO4. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->60%) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:25].[Na+].O.OP([O-])(O)=O.[Na+]>CC#N.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccccc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.5 %

Procedure:
To a solution of 6-chloro-5-phenyl-1H-indole-3-carbaldehyde (90 mg, 0.35 mmol) in MeCN (4 mL), tert-butanol (4 mL) and 2-methyl-2-butene (4 mL, 27.5 mmol) at 0° C. was added a solution of sodium chlorite (327 mg, 4.88 mmol) and sodium phosphate monobasic hydrate (761 mg, 4.88 mmol) in water (4 mL) dropwise. The ice bath was removed and the solution was stirred at room temperature. After 6 hours, additional sodium chlorite (327 mg, 4.88 mmol) and sodium phosphate monobasic hydrate (761 mg, 4.88 mmol) were added as solids and the resulting solution was stirred at room temperature for an additional 14 hours. The reaction mixture was concentrated in vacuo and the aqueous residue was extracted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC to afford the title compound (30.0 mg, 31%) as a white solid. MS (ES+) 271.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (br. s., 1 H), 11.96 (s, 1 H), 8.09 (s, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.48-7.38 (m, 5 H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Cl:17][S:18](O)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccccc2C1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline 45.84 g. (0.2 mole) in 300 ml. of chloroform was added slowly 82.4 ml. (1.24 mole) of chlorosulfonic acid. The solution was stirred and the temperature allowed to come down to 25° C. The solution was quenched in ice water and extracted with chloroform. The extract was washed with water and dried over magnesium sulfate and concentrated. The residue was treated with ether and allowed to stand overnight. The resultant solid was filtered off, added to chloroform, cooled, treated with ether and allowed to stand in the cold for several hours. The resultant solid was again taken up in chloroform and treated with ether to give 2-trifluoroacetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline, m.p. 108°-109° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Br:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[Cl:50]C1C=CC(N)=CC=1>C(O)(=O)C>[Br:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]2[N:23]=[CH:12][N:7]([C:1]3[CH:6]=[CH:5][C:4]([Cl:50])=[CH:3][CH:2]=3)[C:36](=[O:38])[C:25]=2[S:26][CH:27]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2Br)c1N
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3Br)c2ncn1-c1ccc(Cl)cc1
Yield: 73 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-bromophenyl)thiophene-2-carboxylate (150 mg, 0.48 mmol), triethyl orthoformate (0.64 ml), 4-chloroaniline (75 mg, 0.59 mmol), and acetic acid (0.08 ml) were used to give 148.2 mg (0.35 mmol, 73% yield) of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]=O.[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[OH:16].[OH-].[Na+].[C:19]([OH:22])(=O)C>>[Br:8][C:9]1[C:10]2[O:16][CH2:6][O:22][CH2:19][C:11]=2[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CC(=O)O
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(Br)c2c(c1)COCO2
Temperature: 15 °C
Reaction time: 148 h
Yield: 65.5 %

Procedure:
Into a mixture of 229 ml of concentrated sulfuric acid and 620 ml of acetic acid, cooled to 15° C. there is added all at once 311 g of paraformaldehyde (previously washed with 200 ml of acetic acid), followed by 462.6 g (2.23 moles) of 2-bromo-4-chlorophenol. The reaction mixture is stirred for 148 hours at 15° C. It is then neutralized with 3.1 liters of a 7.8N aqueous solution of sodium hydroxide. The precipitate formed is filtered off, dried and then dissolved in toluene. The solution is dried over anhydrous sodium sulfate and then distilled. The residue is stirred in hexane and allowed to crystallize. 364 g of 8-bromo-6-chloro-4H-1,3-benzodioxin are obtained. Yield: 65.5% of theory; M.P.: 108°-110° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](NC(OC)=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[Li+].[OH-:16].Cl.C1[CH2:22][O:21]CC1.CO>>[NH2:1][C:2]1[C:3]([C:22]([OH:21])=[O:16])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: [OH-]
Reactant: COC(=O)Nc1nc(Cl)c(N)nc1N
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Solvent: CO
Product: Nc1nc(N)c(C(=O)O)nc1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of methyl 3,5-diamino-6-chloropyrazine-2-carbamate (5 g, 0.025 mols) in 2:1 THF/MeOH (90 mL) was added 1M LiOH (62 mL, 0.062 mols). After the reaction was stirred at r.t. 72 hrs, 1N HCl (62 mL, 0.062 mols) was added. The reaction was filtered and washed with water (3×10 mL) to give 3,5-diamino-6-chloropyrazine-2-carboxylic acid as white solid 4.3 g (93% yield). LCMS (m/z): 189.1 (MH+); LC Rt=1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:13]S(O)(=O)=O.OS(O)(=O)=O.O=S(=O)=O.II>>[F:1][C:2]1[C:10]([Cl:13])=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: O=S(=O)(O)Cl
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F

Procedure:
The chlorination of the 2,4,5-trifluorobenzoic acid is carried out in the melt, under pressure and/or in a solvent, for example chlorosulphonic acid or oleum, in the presence of halogen transfer agents, for example iodine. 2,4,5-Trifluoro-3-chlorobenzoic acid is obtained in this reaction. However, since the reaction mixture still contains unchanged starting material and some 2,4,5,-trifluoro-3,6-dichlorobenzoic acid, the crude mixture is treated, without intermediate isolation, with thionyl chloride. The desired 2,4,5-trifluoro-3-chlorobenzoyl chloride is then obtained by fractional distillation. However, it is more favorable to carry out the separation by distillation of the acid fluorides.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[CH:13]=[C:14]([C:24](=[O:26])[CH3:25])[CH:15]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]=1[O:18][CH3:19].C(OCC)(=O)C>CN(C)C=O>[C:24]([C:14]1[CH:15]=[C:16]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:17]([O:18][CH3:19])=[C:12]([CH:13]=1)[NH:11][CH2:2][C:3]#[N:4])(=[O:26])[CH3:25]
Reactant: COc1c(N)cc(C(C)=O)cc1C(C)(C)C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(NCC#N)cc(C(C)=O)cc1C(C)(C)C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Bromoacetonitrile (6 ml) and potassium carbonate (1.4 g) were added to a solution of 1-[3-amino-5-(tert-butyl)-4-methoxyphenyl]-1-ethanone (2.0 g, 9.0 mmol) in dimethylformamide (50 ml) and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, washed was performed with water and brine in that order, the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (3.2 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([S:24][CH:25]([CH3:27])[CH3:26])[N:21]=[C:20]([C:28]([OH:30])=O)[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].N.C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([S:24][CH:25]([CH3:27])[CH3:26])[N:21]=[C:20]([C:28]([NH2:33])=[O:30])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(SC(C)C)n3)CC2)c(Cl)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(SC(C)C)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 157.6 %

Procedure:
6-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(isopropylthio)pyrimidine-4-carboxylic acid (Example 180; 200 mg, 0.423 mmol), ammonia solution (2 M in MeOH, 0.43 ml, 0.846 mmol), TEA (0.06 ml, 0.423 mmol), and HATU (161 mg, 0.42 mmol) were combined in DMF (3 ml) and stirred at room temperature for 1 h. The reaction was diluted with EtOAc and water, and the organic portion was washed sequentially with 1 N HCl, saturated sodium bicarbonate, and brine. The organic portion was dried over sodium sulfate, filtered and concentrated to give an off-white solid (312 mg). The crude material was purified by preparatory HPLC using a gradient of 40-70% acetonitrile/water (0.1% TFA) over 14 minutes to give the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:23])(=[O:22])[NH:13][CH:14]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1)=[O:4].[CH3:24][NH:25][C:26]([NH:28][CH3:29])=[S:27]>C(OCC)(=O)C>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:27][C:26](=[N:25][CH3:24])[N:28]2[CH3:29])=[CH:6][C:7]=1[S:12](=[O:23])(=[O:22])[NH:13][CH:14]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CCl)c1ccc(Cl)c(S(=O)(=O)NC2CCCCCCC2)c1
Reactant: CNC(=S)NC
Solvent: CCOC(C)=O
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC3CCCCCCC3)c2)N1C
Product: Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-cyclooctylsulfamoylacetophenone and 1.8 g of 1,3-dimethylthiourea were reacted as prescribed in Example 23. To the reaction mixture were added 30 ml of ethyl acetate and the end product was filtered off. Colorless crystals, melting point: 192° C (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].C([OH:14])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH:10]=[O:14])=[O:11]
Reactant: COc1ccccc1C(C)=O
Reactant: CCO
Product: COc1ccccc1C(=O)C=O

Procedure:
SeO2 (12.4 g., 0.112 mol) was dissolved in 75 ml. of 95% ethanol by warming to 55°. o-Methoxyacetophenone (15.3 g., 0.102 mol) was added in one portion and the mixture refluxed 21 hours. The reaction mixture was treated with activated carbon, filtered over diatomaceous earth, and the filtrate stripped to yield to an oil, 23.2 g. The latter was distilled to yield purified title product, 8.4 g., bp 94°-96°/0.5 mm, which solidified on cooling.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:15][C:16]#[N:17])=[CH:7][C:8]([N+:12]([O-])=O)=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni]>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][C:6]=1[S:15][C:16]#[N:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)c([N+](=O)[O-])cc1SC#N
Reactant: [H][H]
Agent: [Ni]
Product: CC(C)(C)c1cc(N)c(N)cc1SC#N

Procedure:
5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine (prepared in Example QQ-2; 3 g, 12 mmol) was hydrogenated using Raney nickel (0.75 g) in the presence of hydrogen as described in General Method 3. MS(APCI): 222(M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH2:24]=O.[BH4-].[Na+]>>[NH3:2].[CH3:24][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1
Reactant: C=O
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCCC(c2ccc(Oc3ccc(C(N)=O)cn3)cc2)C1
Product: N
Yield: 123.7 %

Procedure:
Combine 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.95 mL of 0.12 M stock solution in methanol, 0.0341 g, 0.115 mmol) and formaldehyde (37% w/w in water, 0.014 mL, 0.156 mmol) and stir overnight. Add sodium borohydride (0.0128 g, 0.338 mmol) and stir. After 4.5 h concentrate the reaction mixture and purify by silica gel chromatography (20:1 ethyl acetate:methanol→2 M ammonia/methanol), then ion exchange chromatography (SCX resin, methanol→2 M ammonia (2M in methanol) to provide 0.02215 g (600%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C18H22N3O2 312.1712, found 312.1718; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.40-7.35 (m, 2H), 7.16-7.11 (m, 2H), 7.02 (d, 1H, J=8.8 Hz), 3.10-3.02 (m, 2H), 2.92 (tt, 1H, J=3.4, 11.7 Hz), 2.43 (s, 3H), 2.27-2.15 (m, 2H), 2.02-1.88 (m, 2H), 1.81 (qt, 1H, J=3.9, 12.7 Hz), 1.57 (dq, 1H, J=3.9, 12.2 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:53]=[N:54][C:55]([CH3:58])=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:53]=[N:54][C:55]([CH3:58])=[CH:56][CH:57]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1ccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)cn1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccc(C)nc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 83A (0.025 g, 0.082 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.014 g, 45% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.88 (s, 9 H), 1.25 (m, 1 H), 1.54 (m, 2 H), 2.32 (m, 1 H), 2.45 (s, 3 H), 2.63 (m, 2 H), 2.89 (m, 3 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.13 (m, 3 H), 4.30 (s, 2 H), 4.55 (d, J=7.35 Hz 1 H), 6.65 (d, J=9.56 Hz, 1 H), 7.07 (m, 5 H), 7.28 (m, 4 H), 7.54 (m, 2 H), 7.86 (m, 5 H), 8.37 (d, J=1.84 Hz, 1 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>C(OCC)(=O)C.CCCCCC>[F:30][C:31]1[CH:32]=[C:33]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])[CH:34]=[CH:35][CH:36]=1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1cccc(F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(F)c1)OCC2c1ccc(C(C)C)cc1
Yield: 67 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-fluorophenyl)boronic acid, the title compound was synthesized in the same manner as in Example 107. Yield: 67%. Melting point: 182-183° C. (ethyl acetate-hexane).