Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Br:15]Br.C(Cl)(Cl)Cl>ClCCl>[Br:15][CH2:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc2cc(C#N)ccc2o1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2oc(C(=O)CBr)cc2c1
Yield: 70.1 %

Procedure:
21.0 g of 2-acetyl-5-benzofurancarbonitrile was dissolved in 300 ml of dichloromethane. With stirring at a temperature of -10° C., 30 ml of dichloromethane solution containing 18.2 g of bromine was added dropwise to the above solution. After gradually warming up to ice-cold temperature, the resulting reaction solution was mixed with chloroform and washed with 10% sodium thiosulfate aqueous solution. After drying the organic layer and subsequent concentration to dryness, the resulting residue was recrystallized from a benzene/n-hexane mixture to obtain 21.0 g of 2-(2-bromo-1-oxoethyl)-5-benzofurancarbonitrile in the form of colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])[CH3:32])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Reactant: Cc1cc(-c2ccn(C[C@H](C)N)n2)ccc1C#N
Product: Cc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4ccncc4)n[nH]3)n2)ccc1C#N
Yield: 39.9 %

Procedure:
The title compound was synthesized from 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (47 mg, 0.25 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (59 mg, 0.25 mmol) using the method of Example 34(d). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 41 mg (40%) of the title compound. 1H-NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 2.52 (s, 3H), 4.32 (m, 2H), 4.53 (m, 1H), 6.59 (d, 1H), 7.15 (m, 1H), 7.36 (s, 2H), 7.53 (d, 1H), 7.58 (m, 2H), 7.70 (m, 2H), 8.53 (br s, 1H), 8.56 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1c([N+](=O)[O-])cc(Cl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(N)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
5-Chloro-2-methyl-1,3-dinitro-benzene (1.96 g, from above) was suspended in methanol (80 mL) and water (20 mL) under N2. Sodium dithionite (5.51 g) was added portionwise and the mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered and washed with methanol. The filtrate was then removed under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and brine (150 mL). The organic layer was dried over magnesium sulfate and evaporated to afford 5-chloro-2-methyl-3-nitro-phenylamine (1.45 g).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[C:11]12([C:21](O)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>>[F:1][C:2]([F:10])([F:9])[C:3]1[NH:4]/[C:5](=[N:8]/[C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])/[S:6][CH:7]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: O=C(/N=c1/[nH]c(C(F)(F)F)cs1)C12CC3CC(CC(C3)C1)C2
Yield: 51.3 %

Procedure:
4-Trifluoromethyl-thiazol-2-ylamine (1.0 g, 6.0 mmol) and 1-adamantanecarboxylic acid (1.0 g, 5.5 mmol) were processed as described in Example 3B to afford 0.932 g (51%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65-1.73 (m, 6H) 1.93 (d, J=3 Hz, 6H) 2.02 (d, 3H) 7.93 (s, 1H); MS (DCI/NH3) m/z 331 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:35][C:36]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([O:47][CH3:48])[C:37]=1[C:38]([NH2:40])=[O:39]>CC(N(C)C)=O.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:40][C:38](=[O:39])[C:37]4[C:36](=[CH:44][C:43]([O:45][CH3:46])=[CH:42][C:41]=4[O:47][CH3:48])[N:35]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCN(C(C)C)CC4)cc3)nc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
A mixture of 4-((4-isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g, 0.97 mmol), NaHSO3 (0.155 g, 1.50 mmol), and p-TsOH (0.019 g, 0.10 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.190 g, 0.97 mmol) in DMA (7 mL). The reaction was stirred at 130° C. overnight. Then, the mixture was diluted with H2O and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.122 g, 30%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 12.02 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.51 (s, 2H), 2.54-2.71 (m, 1H), 2.27-2.44 (m, 8H), 0.95 (d, J=6.4 Hz, 6H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([Cl:30])=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[N:14][C:15]=1[OH:16].Cl>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15]([OH:16])=[N:14][C:13]([CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[N:12][C:11]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Agent: Cl
Solvent: CO
Product: Oc1nc(C2CCNCC2)nc(Cl)c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Into a solution of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate (44.7 g, 100.01 mmol, 1.00 equiv) in methanol (50 ml) was added concentrated hydrochloric acid (50 mL, 12 M). The resulting solution was stirred for 30 min at room temperature. Concentration under vacuum gave 34 g of 5-(1,3-benzothiazol-2-yl)-6-chloro-2-(piperidin-4-yl)pyrimidin-4-ol as a yellow solid, which was used directly for next step without further purification. MS m/z [M+H](ESI): 347.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.[BH4-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(Br)cc(Cl)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2cccc(Br)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 116 g (0.52 mol) of 4-bromo-6-chloro-2-methyl-1-indanone in 950 ml of THF-methanol (2:1, vol.), 38.3 g (1.02 mol) of NaBH4 were added in small portions for 2 h at −5° C. (Caution: temperature must be lower 0° C.). The mixture was stirred overnight at ambient temperature. The resulting mixture was poured on 1000 cm3 of ice and acidified with 10% HCl to pH=4. The organic layer was separated and the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. This combined extract was dried over K2CO3 and evaporated to dryness. To the residue 1500 ml of toluene were added and the resulting toluene solution was treated with catalytic amount of pTolSO3H (ca. 2 g) for 2 h at reflux. Then this mixture was cooled to room temperature and passed through a short Silica Gel 60 column (40-63 μm, d 60 mm, 1 40 mm). This column was additionally eluted with 250 ml of toluene. The combined extract was evaporated to dryness. Fractional distillation gave a mixture of the title indenes, b.p. 104-108° C./5 mm Hg. Yield 100 g (93%) of colorless solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:29][O:30][C:31]1[CH:41]=[CH:40][CH:39]=[C:33]2[C:34]([O:36][C:37](=O)[C:32]=12)=[O:35]>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:37](=[O:36])[C:32]2=[C:31]([O:30][CH3:29])[CH:41]=[CH:40][CH:39]=[C:33]2[C:34]1=[O:35])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: COc1cccc2c1C(=O)OC2=O
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2cccc(OC)c2C1=O)OC
Yield: 20.2 %

Procedure:
In a manner analogous to that described in Example 3 (A), from 0.4 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.178 g of 3-methoxy-phthalic anhydride, there was obtained 0.1 g of [(3-methoxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of a colorless foam.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.CO.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:8][C@H:9]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[C:18]([C:27]([NH:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)NC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@H](N)Cc1cc(F)ccc1F)CC2

Procedure:
A solution of the product (25 mg) from Step A above, 0.5 mL of methanol and 2.5 mL of 4.0M hydrogen chloride in 1,4-dioxane was kept at room temperature for 18 h. The volatiles were removed under a stream of nitrogen, and the residue was triturated with ether. The resultant precipitate was collected and dried in vacuo to afford the title compound as a white powder. LC/MS: 499.1 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](\[C:20]2[CH:19]=[CH:18][C:17]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:22][CH:21]=2)/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C#CCN1CCCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
N-Propargylpyrrolidine (113 mg, 1.04 mmol) and diisopropylamine (0.339 mL, 2.42 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate (300 mg, 0.515 mmol; prepared as described in example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added. The reaction mixture was stirred at ambient temperature for 21 h. Further portions of N-propargylpyrrolidine (113 mg, 1.04 mmol), diisopropylamine (0.339 mL, 2.42 mmol), copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added and reaction mixture was stirred at 50° C. for further 5 h and then evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1-98:2) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][OH:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1
Reactant: OCc1cccc(Cl)c1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Product: Clc1ccc(-c2nc(OCc3cccc(Cl)c3)ncc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-chlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(3-chlorobenzyloxy)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=475 (M++1); Rt=4.92 min; 1H-NMR 400 MHz (CDCl3): δ 5.58 (s, 2H), 7.15 (d, J=9 Hz, 1H), 7.25-7.38 (m, 7H), 7.40-7.50 (m, 2H), 7.58 (s, 1H), 8.48 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH2:12])=[NH:11].[C:14]([N:18]=[C:19]=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH:12][C:19]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[NH:11]
Reactant: CC(C)(C)N=C=O
Reactant: CN(C(=N)N)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1C
Product: CN(C(=N)NC(=O)NC(C)(C)C)c1c(Cl)cccc1Cl

Procedure:
To a mixture of 10.9 g (0.05 mole) of 1-(2,6-dichlorophenyl)-1-methylguanidine and 10 ml xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of sodium carbonate (1.31 g), tetrakis(triphenylphosphine)palladium(0) (0.357 g), 4-tert-butylphenylboronic acid (1.43 g) and 3-bromopyridin-2-amine (1.069 g) in 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.274 g) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:27])[CH2:23][C:24]([NH2:26])=O)[CH2:5][CH2:4]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C(Cl)Cl.C1COCC1>C([O-])(O)=O.[Na+]>[F:1][C:2]([F:29])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:27])[CH2:23][C:24]#[N:26])[CH2:5][CH2:4]1
Reactant: CNc1cc(N(C)CC(N)=O)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNc1cc(N(C)CC#N)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-aminocarbonylmethyl-amino]-4-methylamino-5-nitro-benzoic acid amide (compound IIIa, 45 mg, 0.104 mmol), Burgess reagent (27 mg, 0.11 mmol, +20 mg after 0.5 h, +15 mg after 2.5 h, +20 mg after 16 h), DCM (2 mL) and THF (2 mL) is stirred for 2.5 h at rt, then for 13.5 h at 40° C. and then for 2 h at reflux. The mixture is diluted with sat aq NaHCO3, extracted with EtOAc and the combined organic phases are dried with Na2SO4, filtered and concentrated and directly used in the next step. Yield: 80 mg. HPLC Rt=1.36 min (method A). MS m/z: 414 [M+H]+.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][C:43](=[NH:45])[NH2:44])=[CH:37][CH:36]=1)(=O)=O.CS(O)(=O)=O>N1C=CC=CC=1.C(OCC)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:35]2[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][C:43](=[NH:44])[NH2:45])=[CH:37][CH:36]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)C=Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1

Procedure:
To a solution of 106 g of 4-guanidinobenzoic acid hydrochloride in 1.3 liters of pyridine, while being cooled in ice and stirred, was added 122 g of DCC. After 30 minutes of stirring, to the mixture was added slowly 127 g of 4-(β-amidinoethenyl)phenol methanesulfonate. The resulting clear solution was stirred overnight and the precipitated solid substance was collected by filtration. The solid substance was suspended in 2 liters of water, thoroughly stirred, and filtered. To the filtrate was added at room temperature about 2 liters of saturated aqueous sodium bicarbonate solution. The mixture was stirred and the precipitated crystals were collected by filtration, washed with water, and then with acetone. After air-drying for a short time, the orange-yellow crystals were suspended in 200 ml of methanol and admixed with about 100 g (2 equivalents) of methanesulfonic acid while stirring at room temperature. Ethyl ether was added to the reaction mixture to precipitate crystals which were collected by filtration. The crystals were suspended in methanol and converted again to the carbonate. The carbonate was suspended in 300 ml of ethanol at room temperature and admixed with methanesulfonic acid to turn the suspension into a clear solution. The solution was stirred for a while to precipitate crystals which were collected by filtration at room temperature and thoroughly washed with cold ethanol. The yield was 45 g (18%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Br:25])[C:19](Cl)=[O:20].C(N(CC)CC)C>ClCCl>[Br:25][C:24]1[CH:23]=[CH:22][C:18]([C:19]([N:8]2[CH2:9][C:10]3[N:4]([CH:3]=[CH:2][CH:1]=3)[CH2:5][C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]2=3)=[O:20])=[CH:17][C:16]=1[CH3:15]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: c1cnc2c(c1)NCc1cccn1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ncccc32)ccc1Br
Reaction time: 2.5 h
Yield: 111.4 %

Procedure:
To a stirred solution of the 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (1.0 g) in dichloromethane (10 mL) was added 3-methyl-4-bromobenzoyl chloride (1.39 g) and triethylamine (1.1 mL). After stirring for 2.5 hours, the reaction mixture was washed with water, dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to provide the title product as a tan crystalline solid (2.3 g), which was used without further purification.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2C[CH2:26][NH:25][CH2:24][C:23]2=O)=[CH:18][CH:17]=1.C=O.O>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH3:26])[CH2:12][C:11]2=[O:13])=[CH:20][CH:21]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1CNCCN1c1ccc(Br)cc1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2ccc(Br)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added to a solution of 1-(4-bromophenyl)piperazin-2-one (200.0 mg, 0.7840 mmol, from J&W PharmLab product) and 11.0 M formaldehyde in water (0.21 mL, 2.4 mmol) in methylene chloride (3 mL, 50 mmol) and then the reaction was stirred at rt for 1 hour. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated to provide the product which was used in the next step. LCMS calculated for C11H14BrN2O (M+H)+: m/z=269.0. Found 269.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3,5-Difluorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.[Cl:16]N1C(=O)CCC1=O>CC#N>[Cl:16][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:4]=1[CH:3]([O:2][CH3:1])[O:14][CH3:15])[NH:11][CH2:10][CH2:9][CH2:8]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1Cl)CCCN2
Reaction time: 20 h

Procedure:
A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 200 mg, 0.960 mmol) in MeCN (5 ml) was treated with N-chlorosuccinimide (145 mg, 1.086 mmol), stirred for 20 h. The reaction mixture was concentrated; the residue was treated with Et2O and EtOAc, washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product containing fractions were concentrated. The residue was dissolved in EtOAc, washed twice water (2×) and brine, dried over Na2SO4, filtered and concentrated to give the title compound as a pale yellow oil. (UPLC-MS 1) tR 0.68 min; ESI-MS 243.1 [M+H]+.