Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][N+:16]([O-:18])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C[O-].[Li+].ClCCl.[C:27]([C:29]1[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>O.O1CCCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]=[CH:10][C:11]([CH2:14][C:15]3[CH:28]=[C:27]([C:29]4[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=4)[O:18][N:16]=3)=[CH:12][CH:13]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: O=[N+]([O-])C=Cc1ccc(COc2ccc(F)cc2)nc1
Agent: C[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccc(F)cc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a methanol (5.00 mL) solution of 2-(4-fluoro-phenoxymethyl)-5-(2-nitro-vinyl)-pyridine (50.0 mg, 0.181 mmol) described in Manufacturing Example 72-1-3 was added lithium methoxide (13.7 mg, 0.362 mmol)under nitrogen atmosphere, which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (4.00 mL) tetrachloride (63.7 μL, 0.579 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), after which the system was stirred for 40 minutes at 0° C. Water and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (43.0 mg). To a tetrahydrofuran (5.00 mL) solution of 3-ethynyl-pyridin-2,6-diamine (4.00 mg, 0.030 mmol) described in Manufacturing Example 13-1-3 and this crude product (20.0 mg) was added triethylamine (12.5 μL, 0.090 mmol), which was stirred for 2 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (1.53 mg, 25.4%) as a ditrifluoroacetic acid salt.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][N:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3]1
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Reactant: CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN1CCC(C)(c2cccc(-c3c[nH]nn3)c2)C(C)C1
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 45 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was added commercially available bromopentane (29 mg, 0.19 mmol) and sodium hydrogencarbonate (30 mg, 0.35 mmol). The resultant mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled, poured onto saturated aqueous sodium hydrogen-carbonate solution (100 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to give an off-white gum. The crude product was purified by reverse phase high performance liquid chromatography (condition 1) to give the title compound as a clear oil (33 mg, 57.3%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7]O.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:7][C:6]1[CH:5]=[C:4]([Cl:9])[S:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Cl)sc1Cl
Solvent: ClCCl
Product: Clc1cc(CBr)c(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of (2,5-dichlorothiophen-3-yl)methanol (280 mg, 1.5 mmol) in anhydrous dichloromethane (15 mL) was added dropwise phosphorus tribromide (285 μL, 3.0 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated. The residue was treated with a saturated sodium bicarbonate solution until no more gas evolved. The resultant mixture was extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 3-(bromomethyl)-2,5-dichlorothiophene (125 mg, 34% yield). The product was used without further purification.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([CH2:18][CH2:19]O)[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:54]([OH:57])(=[S:56])[CH3:55].C(=O)([O-])O.[Na+]>O1CCCC1>[C:54]([S:56][CH2:19][CH2:18][N:9]([CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])=[O:11])(=[O:57])[CH3:55]
Reactant: CN(C)CCNC(=O)N(CCO)CCC1CCCCC1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCCN(CCC1CCCCC1)C(=O)NCCN(C)C
Temperature: 5 °C
Yield: 62.7 %

Procedure:
1-(2-Cyclohexyl ethyl)-3-[2-(dimethylamino)ethyl]-1-(2-hydroxyethyl)-urea (Compound 1-1, 0.57 g) and triphenyl phosphine (1.04 g) were dissolved in anhydrous tetrahydrofuran (10 ml) in the nitrogen gas atmosphere and the resulting solution was stirred under cooling with sodium chloride-ice for 30 minutes. Diisopropyl azodicarboxylate (0.78 ml) and a solution of thioacetic acid (0.30 g) in anhydrous tetrahydrofuran (1 ml) were dropwise added to the solution while maintaining the temperature of the solution to a level of not higher than 5° C. After stirring the solution for one hour, saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting oily product was purified through the silica gel column chromatography to give the title compound (Compound 6-1, 0.43 g).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7])[N:9]=1)#[N:27]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Sc3ccccc3)cc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Sc3ccccc3)ccc12

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=377.9.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH3:25])[CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]2[C:9]1=[O:24])(=O)=O.[I-].[Na+].[C:28]([O-:31])(=[S:30])[CH3:29].[K+]>CC(C)=O>[C:28]([S:30][CH2:6][CH2:7][C:8]1([CH3:25])[CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[N:10]2[C:9]1=[O:24])(=[O:31])[CH3:29]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)C1CCCN2CC(C)(CCOS(C)(=O)=O)C(=O)N12
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)SCCC1(C)CN2CCCC(C(=O)OC(C)(C)C)N2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
A solution of 0.77 g tert.butyl hexahydro-2(2-methanesulfonyloxyethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate (diastereomer A) in 20 ml of acetone was treated with 0.3 g of sodium iodide and 0.23 g of potassium thioacetate. The mixture was then stirred at room temperature for 24 hours and subsequently evaporated. After chromatography of the residue on silica gel, there was obtained 0.43 g (59%) of tert.butyl hexahydro-2-(2-acetylthioethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) in the form of an oil.
Reaction SMILES: [Al](C)(C)C.[Cl:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[N:15]([Si](C)(C)C)=[N+:16]=[N-:17].Cl>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]1[NH:17][N:16]=[N:15][N:9]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(Cl)c1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2nnn[nH]2)c1Cl
Temperature: 80 °C

Procedure:
A 2.0 M solution of Al(CH3)3 in toluene (35 mL) was treated with 2,3-dichlorobenzonitrile (8.00 g, 37.2 mmol), azidotrimethylsilane (5.14 g, 44.6 mmol) slowly, and heated at 80° C. for 16 hours behind a blast shield. The mixture was cooled to 0° C. and treated with 2N HCl (100 mL) dropwise over 1 hour. The mixture was allowed to warm to ambient temperature and extracted twice with ethyl acetate (100 mL). The combined organic phases were dried over Na2SO4, filtered through a ½″ pad of silica gel, and the filtrate was evaporated under reduced pressure. The residue was purified by recrystallization from ethyl acetate/hexanes to provide the title compound. MS (DCI/NH3) m/z 215 (M)+; 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8.0 Hz), 7.79 (dd, 1H, J=7.8, 1.7 Hz), 7.92 (dd, 1H, J=8.1, 1.7 Hz).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].O.[NH2:16][NH2:17]>C(O)C.C(OCC)(=O)C>[N+:12]([C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:16][NH:17]2)=[CH:8][CH:9]=1)([O-:14])=[O:13]
Reactant: NN
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c2cc([N+](=O)[O-])ccc12

Procedure:
In two portions of equal size, a total of 2.00 g (10.0 mmol) of methyl 2-fluoro-4-nitrobenzoate and 2.51 g (50.2 mmol) of hydrazine monohydrate in 36 ml of ethanol were heated in a microwave reactor at 120° C. for 2 h. The combined reaction solutions were diluted with ethyl acetate and washed with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. Yield: 1.66 g (purity 95%, 88% of theory)
Reaction SMILES: NC1SC2C3C(CC=2C=1[C:14]([NH2:16])=[O:15])=CC=CC=3.FC(F)(F)C(O)=O.[NH2:24][C:25]1[S:29][C:28]2[C:30]3[C:35]([CH2:36][CH2:37][C:27]=2[C:26]=1[C:39]([NH2:41])=[O:40])=[CH:34][C:33]([Br:38])=[CH:32][CH:31]=3>>[Br:38][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[C:28]1[S:29][C:25]([NH:24][C:14]([NH2:16])=[O:15])=[C:26]([C:39]([NH2:41])=[O:40])[C:27]=1[CH2:37][CH2:36]2
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Reactant: NC(=O)c1c(N)sc2c1CCc1cc(Br)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1sc2c(c1C(N)=O)CCc1cc(Br)ccc1-2

Procedure:
The title compound was prepared by the same procedure as Example 2 except 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-7-bromo-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide trifluoroacetate to give the above title compound as brown solid. ESMS m/z: 367 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])/[C:24]/2=[CH:16]\[C:13]1[NH:12][C:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=2[C:14]=1[CH3:15]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 77 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 24 (71 mg, yield 77%) as a red solid.
Reaction SMILES: C(O)(=O)C(O)=O.C([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[NH:20][CH2:19][CH2:18]2)C1C=CC=CC=1>C(O)(=O)C.Cl>[ClH:37].[Cl:38][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[Cl:37])[CH2:30][CH:21]1[C:22]2[C:17](=[CH:16][C:15]([OH:14])=[C:24]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: CS(=O)(=O)Nc1cc2c(cc1OCc1ccccc1)CCNC2Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc2c(cc1O)CCNC2Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of N-[6-benzyloxy-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-methanesulfonamide oxalate (0.5 g, 0.00085 mol) in 15 mL of acetic acid and 30 mL of conc. HCl was refluxed for 1 h, evaporated to dryness and the residue was crystallized from methanol-ether mixture. Yield 0.23 g (62%). mp 249-250° C. 1H NMR (Me2SO-d6) 300 MHz: δ 10.17 (s, 1H), 9.23 (brs, 2H), 8.84 (s, 1H), 7.75 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.75 (s, 1H), 4.70 (brs, 1H), 3.28-3.43 (brs, 4H), 3.10-3.22 (m, 1H), 2.96-3.04 (m, 1H), 2.90 (s, 3H). MS (ESI): 402 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>CC1CCCO1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc(OCc2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COC(=O)c1ccc(F)cc1Oc1ccc(OCc2ccccc2)nc1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
To 6-(benzyloxy)pyridin-3-ol (1.10 g) in 2-methyltetrahydrofuran (20 mL) was added potassium t-butoxide (5.47 mL, 1.0M in tetrahydrofuran). After stirring for 15 minutes, methyl 2,4-difluorobenzoate (1.035 g) in 2-methyltetrahydrofuran (2 mL) was added and the reaction heated to 75° C. for 1 hour. The reaction was cooled, diluted with ethyl acetate (150 mL), washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (SF40-80 g) eluting with a gradient of 5% to 20% ethyl acetate/hexanes gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Br[C:18]1[C:23]([O:24][CH2:25][C@@H:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=[CH:20][N:19]=1.CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:28][CH:26]2[O:27][C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:23]3[O:24][CH2:25]2)[CH2:15][CH:16]=1
Reactant: Brc1ncccc1OC[C@@H]1CO1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5cccnc5O4)CC3)c2c1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
5-Fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.16 g, 5.37 mmole) and 2-bromo-3-[(2S)-oxiranylmethoxy]pyridine (0.83 g, 3.6 mmole) were combined in DMSO (40 mL). This solution was heated at 75–80° C. under nitrogen for 5 hours. After completion, the reaction was cooled to room temperature and partitioned between 250 mL each of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using first methylene chloride as eluant to remove impurities and then 3% MeOH/CH2Cl2 to elute the product, which was a yellow solid (0.90 g, 56%). The intermediate (0.90 g, 2.01 mmole) was then cyclized in toluene (40 mL) in the presence of palladium (II) acetate (0.02 g, 0.09 mmole), (S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (0.085 g, 0.12 mmole), and potassium carbonate (0.33 g, 2.4 mmole). The heterogeneous mixture was heated to 100° C. for a period of 24 hours. After the mixture cooled to room temperature, the catalysts were removed by filtration and the filtrate was concentrated in vacuum. The resulting crude brown oil was then column chromatographed on silica gel with 3% methanol in methylene chloride to give the desired product as a brown oil (0.23 g, 33%). The oil was crystallized from ethanol with the addition of a solution of oxalic acid (0.05 g) in hot ethanol to give 0.24 g of the (S)-enantiomer of the title compound as a white solid hemioxalate, m.p. 124° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[C:26]([CH:29]=1)[CH:27]=O.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc(-n2cncn2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (50 mg, 0.194 mmol) in DMF (10 mL) is added 5-methoxy-2-1,2,4-triazol-1-yl-benzaldehyde (47 mg, 0.233 mmol) at room temperature. Oxone (119 mg, 0.194 mmol) in H2O (2 mL) is added and the solution is stirred for 1 hour. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried with MgSO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (41 mg, 47%) as a pale brown solid. LCMS (ESMS): m/z 441.20 (M++1).
Reaction SMILES: BrNC(=O)CCC(N)=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[NH:18][C:19](=[O:25])/[CH:20]=[CH:21]/OCC.[NH2:26][C:27]([NH2:29])=[S:28].[OH-].[NH4+]>O1CCOCC1.O>[NH2:29][C:27]1[S:28][C:20]([C:19]([NH:18][C:12]2[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[O:25])=[CH:21][N:26]=1
Reactant: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Reactant: NC(N)=S
Agent: NC(=O)CCC(=O)NBr
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-Bromosuccinamide was added to a mixture of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide in 1,4-dioxane and water at −10° C. to 0° C. to obtain a slurry which was warmed and stirred at 20° C. to 22° C. for 3 hours. Thiourea was added and the mixture was heated to 80° C. After 2 hours, the resulting solution was cooled to 20° C. to 22° C. and concentrated ammonium hydroxide was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0° C. to 5° C. to obtain a solid which was collected by vacuum filtration, washed with cold water, and dried to obtain 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Formula 1c).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:25][N:24]=[C:23]([Br:26])[CH:22]=1.[Br:27]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:25][N:24]=[C:23]([Br:26])[C:22]=1[Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cc(Br)no1
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1onc(Br)c1Br
Reaction time: 24 h

Procedure:
To a solution of 5-amino-4-(3-bromoisoxazol-5-yl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.05 g) in acetonitrile (6 ml) was added N-bromosuccinimide (0.02 g). The mixture was left at room temperature for 24 hours during which time a precipitate formed which was isolated by filtration. Washing with methanol, followed by drying, afforded the title compound as a white solid, m.p. 279° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>CC(O)C>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22]4[NH:26][C:25]5[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=5[N:23]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1
Solvent: CC(C)O
Product: c1ccc2[nH]c(Nc3ccc(Oc4nccnc4C4CCOCC4)cc3)nc2c1
Temperature: 170 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (0.1536 g, 0.566 mmol) and 2-chlorobenzimidazole (0.095 g, 0.623 mmol) in IPA. The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 170° C. for 30 min. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in DCM, to provide N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 388.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:13](=[O:23])[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:30][C:31]1[N:36]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:33][CH:32]=1.CO>ClCCl.Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:13](=[O:23])[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([S:37]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=2)(=[O:39])=[O:38])[CH2:17][CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNCC1O
Reactant: Cc1cccc(S(=O)(=O)Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)N2CCCC(NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(O)C2)n1

Procedure:
To a solution of [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert-butyl ester of Example 2 (1.0 g) in dichloromethane (20 mL) was added saturated sodium bicarbonate (50 mL). To this solution was added 6-methyl-pyridine-2-sulphonyl chloride (6.44 mL of a 0.13 g/mL solution in 9M HCl). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (1.2 g).