Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1cccc(-c2c3c(nn2C2CCCC2)CCNCC3)c1
Yield: 24.5 %

Procedure:
The title compound (34.9 mg) was prepared as in Example 177, Steps C and D, using 204.4 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 234.5 mg of 3-chlorophenylboronic acid. MS (ESI): exact mass calculated for C18H22ClN3, 315.84; found, m/z 316.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.52 (m, 2H), 7.37-7.35 (m, 1H), 7.29-7.26 (m, 1H), 4.46 (m, 1H), 3.43-3.39 (m, 2H), 3.20-3.16 (m, 2H), 2.80-2.76 (m, 2H), 2.06-1.86 (m, 6H), 1.66-1.57 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:25])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].Cl>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:25])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)CCc2ccc(O)cc2)c(O)c1CCC(C)C
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCC(=O)c2ccc(OC)c(CCC(C)C)c2O)cc1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Then, 32.3 g of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone was dissolved in 150 ml of anhydrous acetone, 32.6 g of anhydrous potassium carbonate was added to the solution, and the mixture was stirred for 30 minutes. Then, 17.3 g of methyl α-bromoacetate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 day to effect a reaction. After the reaction, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate, and the solvent was removed from the extract by distillation to obtain 37.0 g (yield=94.6%) of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-methoxycarbonylmethoxyphenyl)-1-propanone in the form of a colorless prism.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([C:15]2[N:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]3[CH:24]=[CH:25][C:26]([Br:28])=[CH:27][C:17]=3[N:16]=2)[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:28][C:26]1[CH:25]=[CH:24][C:18]2[N:19]([C:20]([CH3:21])([CH3:23])[CH3:22])[C:15]([C:6]3[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=3[N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)=[N:16][C:17]=2[CH:27]=1
Reactant: COC(=O)c1ccc(-n2cncn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-benzoic acid methyl ester (100 mg, 0.22 mmol) in dry THF (2 mL) is added Lithium aluminium hydride (LiAlH) (17 mg, 0.45 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with saturated NaHCO3 (10 mL), extracted with EtOAc (3×10 mL). The organic layer is separated, washed with brine (10 mL), dried under anhydrous Na2SO4 (500 mg), and is filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-5% MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford [3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]-methanol (47 mg, 50%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]#[N:17])[CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>O1CCOCC1>[C:16]([C:4]1[CH:3]=[C:2]([NH:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=1)#[N:17]
Reactant: N#Cc1cc(O)c2cc(C(F)(F)F)ccc2n1
Reactant: CC(C)(C)OC(=O)CN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25 mL vial, was placed a solution of 4-hydroxy-6-(trifluoromethyl)quinoline-2-carbonitrile (238 mg, 1.00 mmol, 1.00 equiv) in dioxane (2 mL), PyBrOP (217 mg, 0.47 mmol, 1.10 equiv), triethylamine (354 mg, 3.50 mmol, 2.50 equiv) and tert-butyl 2-aminoacetate hydrochloride (217 mg, 1.30 mmol, 1.30 equiv). The reaction mixture was stirred overnight at room temperature. The reaction was then quenched by the addition of 25 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate. The combined organic layers dried over anhydrous sodium sulfate and concentrated under vacuum. The residue purified by chromatography over a silica gel column with EtOAc/petroleum ether (1:1-1:10). The title compound was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH2:21]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:31]([F:34])([F:33])[F:32])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[OH-].[Na+]>CO.C1COCC1>[F:40][C:35]1[CH:36]=[C:37]([F:39])[CH:38]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21]3)=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:31]([F:34])([F:32])[F:33])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: COC(=O)C[C@H]1CCCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@H]1CCCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of methyl ((3R)-1-{4-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}piperidin-3-yl)acetate (0.045 g, 0.08 mmol) in CH3OH-THF (1:1, v/v) containing 0.5 mL of 1 N NaOH was stirred overnight at ambient temperature. Then it was neutralized with dilute acid and partitioned with ethyl acetate and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was crystallized from ether/petroleum ether to give 0.036 g of title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:37])[CH2:13][N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccc(Cl)cc3)sc2N1
Solvent: Cc1ccccc1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccc(Cl)cc3)sc2N1
Yield: 86.1 %

Procedure:
A suspension of 8.2 g of 5-(2-chlorophenyl)-7-[2-(4-chlorophenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 201°-203° C. and 4.9 g of Lawesson reagent in 160 ml of toluene is stirred at 40°-45° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 4.5 g of 5-(2-chlorophenyl)-7-[2-(4-chlorophenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:29])[C:9](=[O:28])[NH:10][C:11]1[N:12]=[C:13]([C:21]#[C:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:7][CH:8]([CH3:29])[C:9]([NH:10][C:11]1[N:12]=[C:13]([C:21]#[C:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#Cc2ccsc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(N)C(=O)Nc1cc2ccccc2c(C#Cc2ccsc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl-N-[1-oxo-1-[[1-(2-thiophen-3-ylethynyl)isoquinolin-3-yl]amino]-propan-2-yl]carbamate E4a (102 mg, 0.24 mmol) and DCM:TFA (9:1, 2 ml) is stirred at RT for 1 h. The mixture is diluted with toluene (10 ml) and concentrated in vacuo. The product is purified by RP HPLC. Yield: 65 mg (84%). HPLC-MS: M+H=322; tR=1.84 min (*Method—1).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[C:11]([C:14]#[N:15])[C:12]#[N:13])SC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:17][NH2:18]>CCO>[NH2:13][C:12]1[NH:18][N:17]=[C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]=1[C:14]#[N:15]
Reactant: CSC(NC1CCCCC1)=C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1c(NC2CCCCC2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((cyclohexylamino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(cyclohexylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: CC[O-].[Na+].[SH:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([CH3:14])[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[N:7]=1.Cl[CH2:26][C:27]([NH2:29])=[O:28].O>C(O)C>[NH2:13][C:12]1[C:11]2[C:6](=[N:7][C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:9][C:10]=2[CH3:14])[S:5][C:26]=1[C:27]([NH2:29])=[O:28]
Reactant: COc1ccc(-c2cc(C)c(C#N)c(S)n2)cc1OC
Reactant: NC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(C)c3c(N)c(C(N)=O)sc3n2)cc1OC
Yield: 94.3 %

Procedure:
2.1 g (31.4 mmol) sodium ethylate are dissolved in 40 ml absolute ethanol. 3.0 g (10.5 mmol) 2-mercapto-6-(3,4-dimethoxyphenyl)-4-methyl-pyridine-3-carbonitrile and 1.2 g (12.6 mmol) 2-chloroacetamide are added and refluxed for 1 h. Following cooling, 10 ml water are added and the precipitate is sucked off, suck dried and dried in vacuo at 50° C. 3.4 g (94%) 3-amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-b]-pyridine-2-carboxamide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 171 mg, 0.62 mmol) and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (125 mg, 0.62 mmol) in DMF (4 mL) was added DIPEA (0.326 mL, 1.87 mmol). The mixture was heated at 80° C. for 18 h then cooled to rt. Water (16 mL) was added and the resulting suspension was stirred for 1 h. The solids were filtered, rinsed with water (2×), and then dried to afford the crude product which was purified via silica gel chromatography (10% to 50% ethyl acetate in hexanes) to afford the title compound (175 mg, 64% yield) as a pale yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (br s, 1H), 8.26 (s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.00 (br m, 2H), 4.18 (s, 1H), 3.68 (m, 1H), 3.35 (m, 3H), 1.99 (m, 1H), 1.70 M, 1H), 1.57 (m, 1H), 1.23 br s, 9H).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:12])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[C:23](Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+].C(OCC)(=O)C>N1C=CC=CC=1.CCCCCC>[C:23]([O:1][CH:2]([CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:12])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])(=[O:25])[CH3:24]
Reactant: C=CCOC(=O)C(O)CCC(=O)OCc1ccc(OC)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C(CCC(=O)OCc1ccc(OC)cc1)OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Allyl 2-hydroxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate (1.26 g, 4.09 mmol) obtained from Example 2-(2) was dissolved in pyridine (15 ml) at 0° C., and acetyl chloride (481.2 mg, 6.13 mmol) was added thereto. The mixture was warmed to room temperature and stirred for 30 minutes, and then, after cooling to 0° C., a saturated aqueous solution of sodium hydrogen carbonate was added thereto followed by extraction of the product with ethyl acetate. The organic layer was washed with a dilute aqueous solution of hydrochloric acid and with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (60 g) column (eluent; ethyl acetate:hexane=1:5) to afford the title compound (1.36 g, 95% yield) as a colorless oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=1[CH2:26][OH:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=1[CH2:26][O:27][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCc1c(Cl)cncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1cncc(Cl)c1COC1CCCCO1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Dihydropyrane (3.01 mL, 33.2 mmol) and p-toluenesulfonic acid monohydrate (5.06 g, 26.6 mmol) were added to a stirred solution of (3,5-dichloro-pyridin-4-yl)-methanol (1.97 g, 11.06 mmol) in DCM (40 mL). After stirring for 1 d at 40° C. the solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and saturated NaHCO3 solution (50 mL). After extraction of the aqueous layer with DCM (2×50 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with mixtures of hexane and EA) to give the title compound. MS (m/z): 261.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1>CC(O)=O.[Fe]>[Cl:20][C:12]1[C:11]([C:9]2[S:8][C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=3[N:10]=2)=[C:16]([NH2:17])[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 100 °C
Yield: 79 %

Procedure:
Iron powder (6.08 g, 109 mmol) was added to a solution of 4-chloro-2-(2-chloro-6-nitrophenyl)thiazolo[5,4-c]pyridine (3.55 g, 10.9 mmol) in AcOH (100 mL). The reaction mixture was heated at 100° C. for 30 minutes and then allowed to cool to room temperature. The volatiles were removed under reduced pressure and the resultant residue was dissolved in DCM/MeOH and filtered through Celite® washing further with MeOH. The combined washings were concentrated under reduced pressure and the resultant residue was triturated with 10% MeOH in DCM to afford the title compound as an orange/red solid (2.55 g, 79% yield). 1H NMR (400 MHz, CDCl3): δ 8.44 (d, J=5.6 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 6.89 (dd, J=1.2, 7.8 Hz, 1H), 6.73 (dd, J=1.2, 8.3 Hz, 1H), 6.14 (br s, 2H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:7]=2[N:6]=1)([CH3:3])[CH3:2].NN>C(O)C.[Pd]>[CH:1]([NH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:7]=2[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1nc2cc([N+](=O)[O-])ccc2n1C
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC(C)Nc1nc2cc(N)ccc2n1C
Temperature: 80 °C

Procedure:
To a solution of isopropyl-(1-methyl-5-nitro-1H-benzimidazol-2-yl)-amine (2.15 g, 9.2 mmol) and 10% Pd/C (500 mg) in ethanol (60 ml) was added hydrazine (5 ml) and the reaction was heated to 80° C. After TLC showed the starting material to be consumed, the reaction was cooled to rt and passed through a plug of celite. The filtrate was concentrated to give the title compound as an off-white solid. 1H NMR (300 MHz, d6-DMSO) δ 6.75 (d, J=8.1 Hz, 1H), 6.45 (d, J=1.8 Hz, 1H), 6.20 (dd, J=8.1 and 2.1 Hz, 1H), 6.06 (d, J=7.8 Hz, 1H), 4.43 (br s, 2H), 3.96 (m, 1H), 3.35 (s, 3H), 1.19 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH:1]1([N:4]([C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:5][CH2:6][C:7]#[N:8])[CH2:3][CH2:2]1.[C:32](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:4]([C:9]2[C:10]3[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:5][CH2:6][C:7]#[N:8])[CH2:2][CH2:3]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CN(C)CC3)cc1
Yield: 3.6 %

Procedure:
3-(Cyclopropyl(2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)propanenitrile (94 mg, 0.23 mmol) was dissolved in methanol (2 mL). Acetic acid (0.013 mL, 0.23 mmol) was added followed by formaldehyde (0.017 mL, 0.23 mmol). The reaction mixture was stirred at room s temperature for 15 minutes and sodium cyanoborohydride (14.25 mg, 0.23 mmol) was added. The reaction mixture was concentrated under reduced pressure, filtered and purified by preparative HPLC (acidic system) yielding 3-(cyclopropyl(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)propanenitrile (3.50 mg, 3.16%) as acetate salt.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:24]([F:39])[CH:23]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[C:24]([F:39])[CH:23]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)cn2CC(N)=O)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of benzyl (4-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}-2-fluorophenyl)carbamate (28.0 g) in tetrahydrofuran (280 mL) was added trifluoroacetic acid anhydride (196 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, ethanol (140 mL) and 4N aqueous sodium hydroxide solution (40 mL) were added to the residue, and the mixture was stirred at room temperature for 4 hr. The solvent was concentrated under reduced pressure to 1/3, water was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1→9/1) to give the title compound (12.1 g, 51%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CCO>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(-c2nsc(Cl)n2)cc1
Solvent: CCO
Product: Cc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-3-p-tolyl-1,2,4-thiadiazole (900 mg, 4.27 mmol) and piperazine (1.84 g, 21.4 mmol) in 25 mL EtOH were heated to reflux and stirred for 1 h at this temperature. The resulting yellow solution was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica eluting with a gradient formed from DCM, MeOH and NEt3 to yield after evaporation of the product containing fractions 1.1 g (99%) of the title compound as light yellow solid. MS (m/e): 261.3 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:17])[CH3:18])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(OC(C)C)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCC(c2cccc(OC(C)C)c2)CC1
Temperature: 60 °C
Yield: 99.1 %

Procedure:
N-Ethyl-1,2,3,6-tetrahydro-4-(3-(1-methylethoxy)phenyl)pyridine (Preparation 44, 2.0 g, 8.16 mmol) was dissolved in ethanol (20 ml) and 5% palladium on carbon (0.2 g) was added. The suspension was heated at 60° C. under hydrogen (20 psi) for 5 h. The mixture was cooled and the solid was removed by filtration through Arbocel™, washing the resultant cake with ethyl acetate. The filtrate was concentrated in vacuo to give the title compound as an oil (2.0 g, 99%) which was used without further purification.