Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.[OH-].[Na+]>CO.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:20]\[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: O=Cc1cccnc1
Reactant: COc1cc2c(cc1N1CCN(C)CC1)CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2c(cc1N1CCN(C)CC1)C/C(=C\c1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-methoxy-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-one 253 (0.1 g, 0.384 mmol) in MeOH/H2O (1:1) was added nicotinaldehyde (0.049 g, 0.461 mmol) and NaOH (0.03 g, 0.768 mmol) was added to the reaction mass, which was then stirred at RT for 6 h. The reaction mass was diluted with chloroform and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-6-methoxy-5-(4-methylpiperazin-1-yl)-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one 254.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([OH:10])=[C:4]([CH:11]([OH:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[CH:11]([OH:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:31]
Reactant: COc1cc(O)c(C(O)c2ccccc2)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)c(Cl)cc1C(O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of the above prepared 4-chloro-2-(hydroxy-phenyl-methyl)-5-methoxy-phenol (1.39 g, 5.25 mmol) in 15 mL acetonitrile were successively added Cs2CO3 (2.22 g, 1.3 eq.) and ethyl bromoacetate (0.67 mL 1.15 eq.) and the mixture vigorously stirred at ambient temperature over night. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left 1.91 g of the title compound as off-white gum, used directly for the next step.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH2:14]Cl)([CH3:13])[C:10]([Cl:12])=O.P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[CH3:1][NH:2][C:3]1[S:6][C:13]([C:9]([CH2:10][Cl:12])([CH2:8][Cl:7])[CH3:14])=[N:5][N:4]=1
Reactant: CC(CCl)(CCl)C(=O)Cl
Reactant: CNC(=S)NN
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNc1nnc(C(C)(CCl)CCl)s1

Procedure:
To a stirred suspension of 34 g of 4-methylthiosemicarbazide in 50 ml of dioxane was added 60 g of α,α-bischloromethyl propionyl chloride, then heated to reflux temperature. Carefully 50 g of phosphorus oxychloride was added and heating continued until HCl evolution ceased. After cooling, the supernatant liquid was decanted from the viscous material that had separated, water was added and the mixture taken to a pH of 10 with sodium hydroxide pellets. No precipitate formed. The solution was extracted with chloroform, the extract was shaken with water then with saturated sodium chloride solution and was then dried over Na2 SO4. The chloroform was removed at reduced pressure and the residue crystallized with a mixture of methylene chloride-petroleum ether to give 27.8 g, m.p. 105°-107° (36%). An analytical sample, m.p. 108°-109°, was prepared from methylene chloride-petroleum ether.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[SH:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][S:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: OCCS
Product: N#Cc1ccc(SCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 4-(2-hydroxyethylthio)benzonitrile. 900 mg of 4-(2-hydroxyethylthio)benzonitrile was reacted via
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([OH:16])[CH:3]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.O>C(O)(=O)C>[OH:16][C:4]1[CH:3]=[C:2]([N:1]2[C:20](=[O:21])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:22])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.50 g (18.0 mmol) of the compound of Step A and 2.81 g (19.0 mmol) of phthalic anhydride in 40 mL of glacial acetic acid was refluxed for 4 hours and stirred overnight at room temperature. About two volumes of water were added dropwise and the resulting solid was filtered and washed with water. The damp solid was taken up in a little ethanol, filtered and washed with a little ethanol and ether, and air dried to give the title compound, 5.1 g (69%), m.p. 295°-298° C. (dec). Anal. Calcd. for C17H8O3N3Cl3 : C, 49.97; H, 1.97; N, 10.28. Found: C, 49.28; H, 1.95; N, 10.06.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[CH3:13][NH2:14]>>[CH3:13][NH:14][CH:11]1[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: CN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Anhydrous glucose (36.00 g; Aldrich Chemical Company) is weighed into a glass liner. The glass liner is placed into a dry-ice bath and methyl amine gas (68.00 g; Matheson) is condensed into the glass liner. The liner is then loaded into a rocking autoclave (500 ml capacity). The autoclave is heated to 50° C. and rocked for 5 hours at 50° C. under 600 psig nitrogen to form the adduct (N-methylglucosylamine). The reaction is then cooled in a dry-ice bath. The autoclave is then vented cold. Raney nickel (7.2 g of a 50% suspension in water, W/2 type, Aldrich Chemical Company) is added. The reaction is heated to 50° C. under 500-600 psig hydrogen and is rocked for 16 hours. The reaction is cooled in dry-ice bath and vented and purged with nitrogen. The reaction solution is pressure filtered through a Zeofluor filter (PTFE, 47 mm, 0.5 micron filter) with a 4 inch bed of Celite 545 (Fisher Scientific Company). The filtrate is concentrated under a stream of nitrogen to give 8.9 g of white solid. The Celite plug is washed with about 300 mls of water and the water is stripped on a rotary evaporator to give 18.77 g of white solid. The two solids are combined as they are analyzed to be of similar composition (90+ purity by GC analysis). The product is N-methyl glucamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:14]/[CH2:13][C:12]([CH3:17])([CH3:16])[CH3:11])/[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CC(C)(C)CC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1
Yield: 71.3 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chlorobenzyl cyanide (4.5 g, 30 mmol) was reacted with 3,3-dimethyl-butyraldehyde (Aldrich) (3 g, 30 mmol), methanolic solution (25 wt %) of sodium methoxide (7 mL, 30 mmol) in methanol (130 mL) at room temperature for 3 h to give (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile as a colorless oil (5 g, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:29][N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:27][C:26]1[C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][N:30]([CH3:29])[C:31]4=[O:35])=[CH:7][C:6]=3[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]2)=[N:22][CH:23]=[C:24]([CH3:28])[CH:25]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 26.7 %

Procedure:
Using N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (187 mg) described in Preparation Example 226 and 1-methylimidazolidin-2-one (40 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (52 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:13](O)CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]1[O:11][CH2:12][CH2:13][CH2:1][O:2]1
Reactant: COC(=O)CCCC(OC)OC
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)CCCC1OCCCO1
Temperature: 25 °C
Yield: 103.9 %

Procedure:
Methyl 5,5-dimethoxyvalerate (20.0 g, 0.114 mol), propane-1,3-diol (13 g, 0.17 mol) and para-toluene sulphonic acid (2.17 g, 0.0114 mol) were heated under Dean-Stark conditions in toluene (100 ml) for 4 h. The mixture was cooled to room temperature and diluted with diethyl ether (100 ml) and then neutralized with solid sodium bicarbonate. The solid was filtered and the filtrate evaporated to give a pale yellow oil (22.3 g). A 10 g portion of this was then purified by silica gel chromatography (eluent 30% EtOAc:hexane) which gave the title compound as a colourless oil (6.82 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]([C:10]1[C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[S:13][C:14]=1[NH2:15])=[O:9])[CH3:6].O>N1C=CC=CC=1>[CH2:5]([O:7][C:8]([C:10]1[C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[S:13][C:14]=1[NH:15][C:1](=[O:3])[CH3:2])=[O:9])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (62 mL) was added dropwise to a stirred solution of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (125 g) in pyridine (750 mL) on an ice bath. After stirring at room temperature for 30 minutes, the solution was poured into water (2.2 L). The resulting solid was collected by filtration and washed with water, and then was dried overnight at 55° C. to provide the title compound (140 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])(=[O:10])=[O:9])[CH2:5][C:4]2[CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[S:22][C:3]1=2.[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1([CH3:28])[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])(=[O:10])=[O:9])[CH2:5][C:4]2[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[S:22][C:3]1=2
Reactant: CCOC(=O)c1cc2c(s1)C(C)(C)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cc(C(=O)O)sc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of ethyl 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (32.6 g, 76.8 mmol) in THF (853 mL) was added 1.0 M aqueous LiOH (307 mL, 307 mmol) and the reaction mixture stirred overnight at room temperature. The solution was concentrated and the residue dissolved in water (100 mL) and neutralized with 1.0 M aqueous HCl (307 mL). The resulting precipitate was collected via vacuum filtration to afford white solid (29 g, 95%). LCMS (FA) ES+ 397; 1H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 8.08 (dd, J=7.6, 1.6 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz, 1H), 7.95-7.86 (m, 2H), 7.49 (s, 1H), 4.36 (s, 2H), 3.40 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(=O)O
Reactant: Nc1cc(Br)cnc1N
Product: CCc1nc2cc(Br)cnc2[nH]1
Yield: 45 %

Procedure:
4 g of 5-bromopyridine-2,3-diamine in 40 ml of propionic acid is heated at 140° C. in a flask until the diamine has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness. The residue is suspended in water, filtered off with suction and purified by means of column chromatography (gradient EA: methanol 5-40% in 30 min), giving 2.25 g of 6-bromo-2-ethyl-3H-imidazo[4,5-b]pyridine as yellowish solid (yield 45%, content 98%); MS-FAB (M+H+)=228.0; Rf (polar method): 1.27 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](CC=C)[C@H:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:7]1)=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>[Ru](Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCN1CCN(C(=O)OCC)C[C@H]1c1ccc(Cl)cc1
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN[C@H](c2ccc(Cl)cc2)C1
Temperature: 100 °C
Reaction time: 93 h
Yield: 38.8 %

Procedure:
To (R)-ethyl-3-(4-chlorophenyl)-4-(2-propenyl)hexahydro-1-pyrazinecarboxylate (212 mg, 0.69 mmol) produced in Example 24, distilled water (2 mL), conc. hydrochloric acid (71 mg, 1.0 equivalent) and ruthenium chloride (7 mg, 0.04 equivalent) were added. The mixture was stirred at 100° C. for 93 hours. After toluene (2 mL) was added thereto, the formed insolubles were separated by filtration and washed with toluene (2 mL) and distilled water (2 mL). To the filtrate, 30 wt % aqueous solution sodium hydroxide (110 mg, 1.2 equivalents) was added. The organic layer and aqueous layer were separated, and the organic layer was washed twice with distilled water (4 mL). The obtained organic layer was concentrated and dried under vacuum, to obtain 72 mg of the title compound as pale brown oil (yield: 38%, chemical purity: 92.6 area %). The retention time in the chemical purity analysis method was 2.9 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24](=O)[CH3:25].[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:24][CH3:25])[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNCc2ccccc2)COC1(C)C
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1ccccc1)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 17 h
Yield: 18 %

Procedure:
To a stirred solution of (S)-4-(benzylamino-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (800 mg) at r.t. in methanol (10 ml) under an argon atmosphere were added acetaldehyde (0.70 ml), ZnCl2 (1.36 g) and NaBH3CN (0.47 g). The mixture was warmed to 50° C. and stirring at that temperature was continued for 17 h. The mixture was cooled to r.t. and partitioned between ammonium chloride solution and dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/ethyl acetate=1:1) to give (S)-4-[(benzyl-ethyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (160 mg, 18%) as colorless oil. MS (ISP): 293.5 ([M-tBu+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18](O)=[O:19].C[CH2:23][N:24]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN.Cl>CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:24][CH3:23])=[O:19]
Reactant: Nc1cc2nn(-c3ccc(F)cc3)c(C(=O)O)c2cc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c2cc(Br)c(N)cc2nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 6-amino-5-bromo-2-(4-fluorophenyl)-2H-indazole-3-carboxylic acid (1.0 g, 2.8 mmol) in dry DMF (500 mL) were added EDCI (1.1 g, 6.2 mmol) and HOBT (0.5 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 1 h, and then Et3N (5 mL) and MeNH2.HCl (0.9 g, 14.3 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and 300 mL Na2CO3 (a.q.) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (PE:EA=3:1) to give 6-amino-5-bromo-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (0.8 g, yield: 74%). 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.55˜7.58 (m, 2H), 7.20˜7.26 (m, 2H), 6.98 (s, 1H), 5.75 (s, 1H), 4.32 (s, 2H), 2.98 (d, J=4.8 Hz, 3H). MS (M+H)+: 363/365.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)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>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:28]#[C:27][CH2:26][CH2:25][OH:29])[CH:17]=3)[N:12]([CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)ccc21

Procedure:
A solution of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxamide [Example 1] (0.12 g), copper iodide (0.020 g), Pd(PPh3)2Cl2 (0.0067 g) and 3-butyn-1-ol (0.030 mL) in 10 mL diethylamine is stirred at room temperature for 18 h. The reaction is partitioned between ethyl acetate and H2O. The aqueous layer is extracted 3× with ethyl acetate. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L)) affords the desired product which is recrystallized with CH2Cl2/hexanes (0.059 g, 56%). Physical characteristics are as follows: m.p. 227-229° C.; 1H NMR (300 MHz, DMSO-d6) δ9.90, 8.18, 7.93, 7.40, 4.97, 4.55, 4.24, 3.62, 2.62; IR (drift) 3238, 3176, 1671, 1614, 1594, 1551, 1493, 1470, 1411, 1321, 1281, 1045, 825, 808, 733 cm−1; MS (ESI) m/z 396.0 (M+H)+; HRMS (FAB) calcd for C21H18ClN3O3+H1 396.1115, found 396.1114.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].O>CN(C)C=O>[NH2:19][C:18](=[N:17][C:14]1[S:15][CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][NH:4][C:31](=[O:32])[CH2:30][O:29][CH3:28])[N:11]=2)[N:13]=1)[NH2:20]
Reactant: COCC(=O)Cl
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reaction time: 2.5 h

Procedure:
To a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (4.7 ml) in N,N-dimethylformamide (60 ml) was added a methoxyacetyl chloride (0.9 ml) under ice-cooling and the mixture was stirred for 2.5 hours at the same temperature. The reaction mixture was added to water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-methoxyacetylaminomethylpyridin-2-yl)thiazole (0.86 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.[CH:13]([C@H:16]1[NH:21][CH2:20][CH2:19][N:18]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=3[N:24]=[C:17]12)([CH3:15])[CH3:14].O>ClC(Cl)C.C(O)(C)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]3[C:22]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=4[N:24]=[C:17]3[C@H:16]2[CH:13]([CH3:15])[CH3:14])[N:7]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(Cl)n1)[C@@H]3C(C)C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of methyl 2,4-dichloropyrimidine-5-carboxylate (27 mg, 0.13 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was cooled to 0° C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for 1 h, a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (30 mg, 0.09 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was added slowly at 0° C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (34 mg, 77.3% yield) as a solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH3:7].O.[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[C:11]2[CH:10]=[CH:13][CH:9]=[CH:10][C:11]=2[NH:7][CH2:9][CH2:13]1
Reactant: C1CCOC1
Reactant: N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: c1ccc2c(c1)NCCO2
Yield: 91 %

Procedure:
2H-1,4-benzoxazin-3-(4M-one (4.5 g, 30 mmol) was added portionwise to a stirred suspension of lithium aluminium hydride (4.7 g, 120 mmol) in THF (100 ml) and heated at reflux for 3 h. The mixture was cooled in an ice/water bath and ammonia solution (8 ml) and water (40 ml) were added while stirring. The mixture was filtered through Celite and reduced. Chromatography (50% EtOAc/50% 60-80 petroleum ether) afforded benzomorpholine (3.7 g, 91%) as a pale brown oil.