Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.75 min; [M+H]+=437.22.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC(OC)=CC=2)[O:40][C:39]=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([O:40][CH3:39])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1
Yield: 100 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-methoxy-2-phenyl-chromen-4-one was reacted to give the title compound (80 mg, 100%) as a colourless oil. LCMS (Method A) RT=4.88 min, [M+H]+=498.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH2:3]1.P(Cl)(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][C:5]1[C:4]2[CH2:3][C:2]([CH3:13])([CH3:1])[CH2:11][CH2:10][C:9]=2[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CCc2nc[nH]c(=O)c2C1
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2ncnc(Cl)c2C1
Yield: 75 %

Procedure:
To 6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6.41 g, 36 mmol) in chloroform (10 mL) added phosphorus oxychloride (10 mL) and refluxed for 2 hours. The mixture was concentrated to an oil, then diluted with ethyl acetate (80 mL) and washed with saturated sodium carbonate (50 mL) and brine (25 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated, then the residue purified by silica gel column chromatography (ethyl acetate/hexanes, 1:8) to give 4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (5.3 g, 75% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): 8.72 (s, 1H), 2.52 (t, 2H), 2.14 (s, 2H), 1.48 (t 2H), 0.93 (s, 6H); MS (EI) for C10H13ClN2: 197 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[CH3:18].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:19]([C:20]#[N:21])([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: Cc1ccc(CC#N)cc1C
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cool a solution of sodium bis(trimethylsilyl)amide (723 mL, 1M in tetrahydrofuran, 723 mmol) to 0° C. in an ice bath. Add a solution of 3,4-dimethylphenylacetonitrile (50.0 mmol) in tetrahydrofuran (130 mL) over about 1.5 hours. When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir. After 2 hours, transfer the above solution via cannula into a cooled (-50° C.) solution of ethyl bromoacetate (126 g, 757 mmol) in tetrahydrofuran (250 mL). After the transfer is complete, allow the reaction mixture to warm to ambient temperature. After 18 hours, dilute with diethyl ether (500 mL) and extract with water, 1M hydrochloric acid solution, saturated aqueous solution of sodium bicarbonate, and then brine. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Recrystallize the residue from diethyl ether to give the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43])[CH3:36]>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:40]4[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[C:38](=[O:43])[CH2:39]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN1CCNCC1=O
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCN1CCN(c2nccc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc(Cl)cc5)c4s3)n2)CC1=O
Temperature: 100 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (15.0 mg, 0.029 mmol) in DMF (0.4 mL) was added 1-ethylpiperazin-2-one (7.4 mg, 0.058 mmol). The reaction mixture was heated at 100° C. overnight. Reaction mixture was concentrated in vacuo and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the product. LCMS-ESI+: calc'd for C31H35ClN5O4S: 608.2 (M+H+); Found: 608.2 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[C:26](=[O:34])[CH:25]=[N:24]2)=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].CC(O)(C)C>O>[CH2:30]([N:27]1[C:26](=[O:34])[CH:25]=[N:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N:16]3[CH2:14][CH2:13][N:4]([C:5]4[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=4)[CH2:3][CH2:2]3)=[CH:22][CH:21]=2)[C:28]1=[O:29])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCn1c(=O)cnn(-c2ccc(N)cc2)c1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCn1c(=O)cnn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A mixture of 27.1 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 29 parts of 2-(4-aminophenyl)-4-butyl-1,2,4-triazine-3,5(2H,4H)-dione, 18.4 parts of sodium hydrogen carbonate and 350 parts of 2-methyl-2-propanol was stirred overnight at reflux temperature. After cooling, 200 parts of water was added. The precipitated product was filtered off and crystallized from 4-methyl-2-pentanone. The product was filtered off and dried in vacuo at 75° C., yielding 19.8 parts (41.3%) of 4-butyl-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; mp. 181.3° C. (int. 29).
Reaction SMILES: [N:1]([O-:3])=[O:2].F[B-](F)(F)F.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.O>C(#N)C>[N+:1]([C:13]1[C:14]([OH:18])=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][NH:9]2)([O-:3])=[O:2]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1c(O)ccc2[nH]ncc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Under a nitrogen atmosphere, a solution of tetrafluoroborate nitrite (110 mg, 0.783 mmol) in acetonitrile (3 ml) was added dropwise to a suspension of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in acetonitrile (4.0 ml) at −35° C. over a period of 10 minutes, and the resulting mixture was slowly heated to 0° C. After 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The residue purified was concentrated under reduced pressure and the resulting residue was washed with ethanol/diisopropyl ether by repulping to obtain 4-nitro-1H-indazol-5-ol (59.8 mg, 45%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[F:17])[C:11]([NH2:13])=[O:12].S(=O)(=O)(O)O>>[Cl:1][CH2:2][C:3]1[N:13]=[C:11]([C:10]2[CH:14]=[CH:15][C:16]([F:17])=[C:8]([F:7])[CH:9]=2)[O:12][CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: Fc1ccc(-c2nc(CCl)co2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With stirring, 500 mg (3.94 mmol) of 1,3-dichloroacetone and 619 mg (3.94 mmol) of 3,4-difluorobenzamide are heated at +135° C. for 1 h. After cooling to RT, the mixture is allowed to stand at this temperature for 90 min 1.0 ml of conc. sulphuric acid is then added, and the mixture is stirred at RT for a further 15 min. The entire mixture is then poured onto 50 ml of ice. Initially, a viscous oil is formed. The mixture is stirred for 60 min, during which time a precipitate is formed which is filtered off with suction, dried under high vacuum and then purified chromatographically on silica gel 60 (mobile phase: isohexane/ethyl acetate 10:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[C:5]([CH3:13])=[CH:4][C:3]=1[CH:14]([CH3:17])[CH:15]=[CH2:16].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:9]=[CH:10][CH:11]=[CH:12]2)[C:5]([CH3:13])=[CH:4][C:3]=1[CH:14]([CH3:17])[CH:15]=[CH2:16])(=[O:20])[CH3:19]
Reactant: C=CC(C)c1cc(C)c(-n2cccc2)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CC(C)c1cc(C)c(-n2cccc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A few drops of pyridine are added to a solution of 26.7 g (0.12 mole) of 3-[2-hydroxy-5-methyl-4-(pyrrol-1-yl)-phenyl]-1-butene in 370 ml of acetic anhydride and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice and extracted three times with methylene chloride. The methylene chloride phases are washed with dilute sodium bicarbonate solution, then with water, until neutral, are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Filtration over a little silica gel with methylene chloride yields 3-[2-acetoxy-5-methyl-4-(pyrrol-1-yl)-phenyl]-1-butene, Rf (toluene/ethyl acetate=10:1): 0.55.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C.[OH-].[Na+]>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[C:5]([OH:7])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.4 %

Procedure:
To a suspension of 3,4-dihydroxybenzoic acid (25.4 g, 0.17 mole) in ethanol (250 ml), 5N NaOH aq. (270 ml) and benzyl chloride (102 g, 0.81 mole) were added, and the mixture was reacted with stirring for 6 hours under reflux. The reaction mixture was cooled to room temperature, allowed to stand at same temperature overnight and acidified with conc. hydrochloric acid (40 ml). The precipitate was filtered, washed with hot ethanol and dried under reduced pressure to give 38.2 g of 3,4-dibenzyloxybenzoic acid as pale yellow crystals having a m.p. of 184°-186° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11](OC)=[O:12])[CH:8]=2)[NH:3]1.O1CCCC1.C(O)C.[BH4-].[Li+]>C(O)C>[OH:12][CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1Cc2cc(CO)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To an ice-cooled mixture of methyl 2-oxoindoline-5-carboxylate (0.5 gram, 2.6 mmol) in a tetrahydrofuran/ethanol mixture (15:0.3 mL) was added lithium borohydride (115 mg, 5.2 mmol) in one portion. After 30 min, another portion of lithium borohydride (100 mg, 4.5 mmol) was added and the reaction solution was stirred for 4 h at room temperature. A third portion of lithium borohydride (200 mg, 9.2 mmol) and ethanol (0.3 mL) were added and the reaction solution was stirred for 14 h at room temperature. The reaction was quenched with water (10 mL) and an aqueous saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/methanol, (10:1) as the eluent to give 140 mg (33% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 10.3 (br s, 1 H), 7.14 (s, 1 H), 7.09 (d, J=8 Hz, 1 H), 6.74 (d, J=8 Hz, 1 H), 5.03 (t, J=6 Hz, 1 H), 4.41 (7, J=6 Hz, 2 H), 3.44 (s, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[F:31])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: Fc1cc(Cl)ccc1CBr
Product: Cc1nc(-c2ccn(Cc3ccc(Cl)cc3F)n2)sc1C(=O)NCc1cccnc1
Yield: 51 %

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-chloro-2-fluoro-benzene as described in Example 49 and isolated as a white solid (0.075 g; 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56-8.58 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.46 (d, J=4 Hz, 1H), 7.26-7.31 (m, 1H), 7.10-7.17 (m, 3H), 6.85 (s, 1H), 6.07-6.15 (m, 1H), 5.36 (s, 2H), 4.62 (d, J=8 Hz, 2H), 2.75 (s, 3H). MS (M+H)+=442.1; Rt=1.35 min; HRMS (M+H)+=442.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]2[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=2[CH2:22][CH:21]1[OH:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[CH2:22][CH:21]2[OH:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1c2ccccc2-c2ccccc2CC1O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1c2ccccc2-c2ccccc2CC1O

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 5-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol hydrochloride (Example 2-A), the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCl3/MeOH.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Cl:20]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([Cl:20])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[C:8]([O:18][CH3:19])[CH:9]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OC)c2c(Cl)cn(C3CC3)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred solution of 1.29 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 13 ml of THF was added 801 mg of N-chlorosuccinimide and the mixture was stirred at 60° C. for 2 hrs. After diluted with EtOAc, the mixture was washed successively with water and saturated brine, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography to afford 1.03 g of ethyl-3-chloro-1-cyclopropyl-4-(methoxy)-1H-indole-6-carboxylate as a colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH2:13])[CH:7]=[CH:6][N:5]=1.[Cl:14][C:15]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[C:16]=1[C:17](Cl)=[O:18]>CN(C=O)C>[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH:13][C:17](=[O:18])[C:16]2[C:20]([Cl:26])=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:15]=2[Cl:14])[CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: Nc1ccnc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Cl)c2[N+](=O)[O-])c(Cl)c1
Reaction time: 0.33 h
Yield: 46.4 %

Procedure:
NaH (0.46 g, 11.6 mmol, 60% dispersion in mineral oil) was added in one portion to a cooled (0° C.) solution of 2-chloro-3-nitropyridin-4-amine (1.00 g, 5.8 mmol) in DMF (15 mL). The mixture was stirred for 20 mins and then a solution of 2,6-dichloro-4-cyanobenzoyl chloride (0.68 g, 2.9 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 4 hours and then poured onto ice-water (20 mL). The resulting precipitate was collected by filtration and then the filtrate was extracted by EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was combined with previously collected precipirate and the material was purified by silica gel column chromatography (MeOH:CH2Cl2 1:10) to afford N-(2-chloro-3-nitropyridin-4-yl)-2,6-dichloro-4-cyanobenzamide (0.5 g, yield: 23%). LCMS (ESI) m/z: 372.6 [M+H+]
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](I)=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Br:1][C:2]1[C:3]2[N:4]([C:9]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2cnc3c(Br)cc(Cl)nn23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
A pressure bottle charged with a mixture of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (1.4 g, 3.91 mmol), 4-fluorophenylboronic acid (0.558 g, 3.98 mmol), dioxane (20 mL), and tetrakis(triphenylphosphine)palladium(0) (0.452 g, 0.39 mmol), and K3PO4 (2.49 g, 11.72 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 85° C. for 8 h. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (0-20% EtOAc/CH2Cl2, 1.2 L) to give the product (0.56 g, 44%). LC/MS: Rt=3.22 min. LC/MS (Condition A): 325.83/327.83/329.83.
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:39]=[CH:38][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1.[CH3:40]I>CCCCC.O1CCCC1>[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C@H:7]([CH3:18])[CH2:6][N:5]1[C@H:19]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])=[CH:38][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:40])[CH:21]=1
Reactant: CI
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), and tetrahydrofuran (10 mL) was added. The product from Example 11, 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 δL, 568 mg, 4 mmol) was added. The reaction mixture was sealed under nitrogen and stirred for 6 h at ambient temperature. The reaction mixture was evaporated to dryness, and the residue was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, the aqueous portion extracted with ethyl acetate (2×10 mL) and the combined organic extracts were dried over anhydrous sodium sulfate. The organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane yielded 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc. for C32H40FN3O2 0.25 H2O: C, 73.60; H, 7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84% 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[CH2:5]([O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](Cl)[C:10]=1C#N)[CH3:6]>CCO>[CH2:5]([O:7][C:8](=[O:19])[C:9]1[CH:14]=[C:13]([CH3:15])[N:1]=[C:2]([SH:3])[C:10]=1[C:11]#[N:12])[CH3:6]
Reactant: NC(N)=S
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1C#N
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc(S)c1C#N
Yield: 50.4 %

Procedure:
Thiourea (339 mg, 4.46 mmol) was added to a solution of 2-chloro-3-cyano-6-methyl-isonicotinic acid ethyl ester (500 mg, 2.23 mmol) in EtOH (25 mL) at room temperature. The mixture was heated to reflux for 24 h. The mixture was cooled (crystallization began upon cooling) to room temperature. The solid was collected by vacuum filtration giving 3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester (250 mg, 50%) as a yellow orange solid.