Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[C:12](=N)([O:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C>[C:1]([NH:9][N:10]=[C:12]([O:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CCCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: CCCCC(=NNC(=O)c1ccncc1)OCC
Temperature: -10 °C
Yield: 51.2 %

Procedure:
A mixture of 2.46 g (17.9 mmole) of isonicotinic hydrazide and 50 ml of ethanol was stirred at -10° C. as a solution of 2.52 g (16.6 mmole) of ethyl valerimidate hydrochloride, in 46 ml of ethanol was added dropwise under protection from moisture. The mixture was maintained at -10° C. for three hours and then at 5° C. overnight. The filtered solution was concentrated, and the residue was flash chromatographed on silica gel (elution with 2.5% methanol in CH2Cl2) to provide 2.12 g (50%) of the titled compound as an oil which goes to a waxy solid at 5° C., homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 250 (M+1)+. NMR suggested that the product is a mixture of syn and anti-isomers.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(/C=C/c2ccccc2)cc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1c(O)cc(OC)cc1/C=C/c1ccccc1
Yield: 94.5 %

Procedure:
Dissolve compound 6 (6 g, 0.0201 mol) in 50 ml dichloromethane, add drop wise BBr3 solution in methylene chloride (24 ml, 1M) at 0° C., react at room temperature for 1 h. Wash the reaction solution with water, dry over anhydrous magnesium sulfate. Filter the solution and remove the solvent by rotary evaporation, dissolve the residue with petroleum ether/diethyl ether and feed the solution to a silica gel column, evaporate the solvent in eluent to obtain 5.4 g white solid (95%). 1H-NMR (400M, CDCl3) δ (ppm): 3.79 (s, 3H), 3.82 (s, 3H), 6.40 (d, J=2.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 7.15 (dd, J=16 Hz, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.52 (d, J=7.2 Hz, 2H), 10.28 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.C([O:19][N:20]=O)CC(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[OH:19][N:20]=[C:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3][N:2]([CH3:1])[C:8]1=[O:9]
Reactant: CC(C)CCON=O
Reactant: CN1CCc2ccccc2CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCc2ccccc2C(=NO)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (1 eq.) was dissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixture was cooled to 0° C. in an ice bath. NaHMDS (1.1 eq., 1M in THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixture was concentrated then acidified with 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic portion was dried and concentrated to yield a crude product which was purified by silica gel chromatography to give 1-hydroxyimino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one: Mass spectroscopy (M+H)+, 205.1.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[C:16]1[C:21]([C:22]2([OH:26])[CH2:25][O:24][CH2:23]2)=[C:20]([Cl:27])[CH:19]=[CH:18][N:17]=1.CNCCNC.CC([O-])=O.[K+]>[Cu]I.O1CCOCC1>[Cl:27][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:2]2[CH2:3][CH2:4][N:5]3[C:13]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[CH:7]=[C:6]3[C:1]2=[O:14])[C:21]=1[C:22]1([OH:26])[CH2:25][O:24][CH2:23]1
Reactant: O=C1NCCn2c1cc1c2CCCC1
Reactant: OC1(c2c(Cl)ccnc2Br)COC1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: CNCCNC
Solvent: C1COCCO1
Product: O=C1c2cc3c(n2CCN1c1nccc(Cl)c1C1(O)COC1)CCCC3
Temperature: 85 °C
Yield: 41.7 %

Procedure:
A 100 mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 101e (190 mg, 1.0 mmol), 148a (795 mg, 3.0 mmol), CuI (95 mg, 0.5 mmol), DMEDA (88 mg, 1.0 mmol), KOAc (294 mg, 3.0 mmol), and 1,4-dioxane (50 ml). The system was evacuated and then refilled with N2. A reflux condenser was attached to the flask, and the reaction mixture was heated at 85° C. for 15 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 2:1 petroleum ether/ethyl acetate to afford 148b as a yellow solid (156 mg, 42%). MS: [M+H] 374.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH3:13])[C:7]2=[O:14].Cl.[CH3:17][C:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:18]1([CH3:17])[CH2:21][CH2:20][CH2:19]1)[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: CC1(N)CCC1
Reactant: Cn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(NC2(C)CCC2)nc2c(Br)c(F)ccc2c1=O
Yield: 43 %

Procedure:
A solution of 8-bromo-2-chloro-7-fluoro-3-methylquinazolin-4(3H)-one (720, 239 mg, 0.820 mmol), 1-methylcyclobutanamine hydrochloride (Oakwood Products, Inc., West Columbia, S.C., 199 mg, 1.640 mmol), and N-ethyl-N-isopropylpropan-2-amine (314 μL, 1.804 mmol) in DMSO (8.2 mL) was stirred at 80° C. for 1 h. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-40% EtOAc in hexanes to give 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502a, 0.120 g, 0.353 mmol, 43% yield) as a brown amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.74 (s, 3H) 1.89-2.00 (m, 2H) 2.26-2.36 (m, 2H) 2.38-2.49 (m, 2H) 3.46 (s, 3H) 4.72 (br. s., 1H) 6.90 (t, J=8.51 Hz, 1H) 8.06 (dd, J=8.80, 6.06 Hz, 1H). 19F NMR (377 MHz, CDCl3) δ ppm −96.60 (s, 1F). MS (ESI, pos. ion) m/z: 340.0/341.9 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[N+](=[CH2:18])=[N-].C(O)(=O)C>CO>[CH3:18][O:14][C:13]([C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([CH2:2][OH:1])=[C:7]([CH3:8])[C:6]=2[CH:9]=1)=[O:15]
Reactant: C=[N+]=[N-]
Reactant: Cc1c(CO)oc2ccc(C(=O)O)cc12
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2oc(CO)c(C)c2c1

Procedure:
A solution of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid (0.69 g) in methanol (250 ml) was treated with an excess of an ethereal solution of diazomethane. The solution was allowed to stand for 11/2 hours at 0° and then the excess of diazomethane was decomposed by dropwise addition of acetic acid until no further effervescence was apparent. The solution was evaporated and the residue was dissolved in ether. The solution was washed with sodium bicarbonate, dried (Na2SO4) and evaporated to give a quantitative yield of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid methyl ester, m.p. 96°-98° (from ethyl acetate/petrol).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:20][N:21]=2)[N:18]=1>CN(C=O)C>[S:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:19]1[N:17]2[N:18]=[C:13]([O:3][CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1
Reactant: Clc1ccc2nnc(-c3cccs3)n2n1
Reactant: CCOC(=O)C(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1ccc2nnc(-c3cccs3)n2n1
Reaction time: 0.17 h

Procedure:
Sodium hydride (1.5 equiv., 60% in mineral oil) was added at 0° C. to a solution of ethyl 2-hydroxybutyrate (1.5 equiv.) in dry DMF (7 mL) under argon atmosphere and the mixture was stirred for 10 min. To this mixture was added 6-chloro-3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazine (1 mmol) dissolved in DMF (3 mL). After 30 min, TLC showed that all the staring material was consumed. The solution was extracted with ethyl acetate, washed with water twice and concentrated. The crude syrup thus obtained was purified by flash column chromatography to give ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)butanoate.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.O>C(#N)C.CCOC(C)=O>[NH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1
Reactant: COc1ccc(CN[C@H]2CC[C@@H](NS(=O)(=O)c3ccc(-c4ccc(F)cc4F)cc3)CC2)c(OC)c1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H](NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
N-(cis-4-(2,4-Dimethoxybenzylamino)cyclohexyl)-2′,4′-difluorobiphenyl-4-sulfonamide (see ABD787a) (52 mg, 0.10 mmol) was stirred in acetonitrile (3 mL) and water (1 mL) and ceric ammonium nitrate (144 mg, 0.26 mmol) was added. The mixture was stirred at 50° C. overnight and then diluted with EtOAc (15 mL) and washed with water (2×5 mL). The washings were extracted with EtOAc (5 mL) and the combined organics were dried over MgSO4. After evaporation of the solvents, the residue was loaded onto a 1 g SCX column and eluted with MeOH and then 20% 2 M NH3/MeOH in DCM. The resulting material was further purified by chromatography (2 g Isolute II cartridge), eluting with 0-10% 2 M NH3/MeOH in DCM to afford the title compound as an off-white powder (9 mg, 25%). 1H NMR (300 MHz, DMSO-d6): δ 0.86-0.98 (2H, m), 1.09-1.26 (2H, m), 1.55-1.68 (4H, m), 2.40 (1H, br s), 2.87 (1H, br s), 4.12 (1H, br s), 7.22 (1H, td, J=8 Hz, 2 Hz), 7.40 (1H, td, J=10 Hz, 2.5 Hz), 7.65 (1H, q, J=7 Hz), 7.71 (2H, d, J=9 Hz) and 7.85 (2H, d, J=9 Hz). LCMS: (MH)+=367.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]([NH2:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:5][CH:6]([NH:13][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)Cl
Reactant: CCCCCCC(C)N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCC(C)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of acetyl chloride (7.11 mL, 100 mmol) was added dropwise to an ice water-cooled solution of 1-methylheptyl amine (8.30 g, 64 mmol) and triethylamine (20.91 mL, 150 mmol) in TF (100 mL). The resulting mixture was stirred at RT for 1 h, then was diluted with ethyl acetate and washed twice with 10% HCl, twice with sat aq NaHCO3, and then twice with brine. The organic solution was dried (MgSO4), and concentrated to afford 8.13 g N-(1-methylhept-1-yl)acetamide, a 73% yield.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:3]([C:2](=[O:1])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate (38.2 g, 0.147 mol), 4-fluorobenzyl bromide (25 g, 0.13 mol), potassium carbonate (36.6 g, 0.26 mol) and acetonitrile (500 ml) was stirred at 60° C. for 3 hrs. The reaction solution was concentrated under reduced pressure, and water (500 ml) was added. The mixture was extracted with ethyl acetate (500, 200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-10:1, hexane:toluene=1:1) and crystallized from cold hexane to give ethyl 2-((4-fluorophenyl)methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propionate (29.5 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: CN1CCNCC1
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)cc(Cl)c2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C)CC4)ccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-1-benzofuran-2-yl)nicotinonitrile (106 mg, 0.25 mmol) in THF (3 mL) and EtOH (1 mL) was added 1-methylpiperazine (75 mg, 0.75 mmol) and acetic acid (75 mg, 1.2 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added to the reaction mixture and the solution was stirred at room temperature overnight, and concentrated. Aqueous 1N HCl was added and the aqueous phase was extracted with ethyl acetate, basified to pH of 10 by adding sodium carbonate, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and concentrated to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl}nicotinonitrile as a yellow solid (68 mg, 53%). HPLC retention time: 7.0 min.(g); and MS: 511.5 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C@H:15]([N:19]2[CH2:22][C:21]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:20]2)[CH2:14][CH2:13]3)[CH:5]=1.[CH3:28][C:29]1[S:33][C:32]2=[N:34][C:35]([CH2:37][C:38](O)=[O:39])=[CH:36][N:31]2[N:30]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[CH3:28][C:29]1[S:33][C:32]2=[N:34][C:35]([CH2:37][C:38]([N:25]3[CH2:26][CH2:27][C:21]4([CH2:22][N:19]([C@H:15]5[C:16]6[C:12](=[CH:11][C:10]([C:6]7[CH:5]=[C:4]([CH3:3])[N:9]=[CH:8][N:7]=7)=[CH:18][CH:17]=6)[CH2:13][CH2:14]5)[CH2:20]4)[CH2:23][CH2:24]3)=[O:39])=[CH:36][N:31]2[N:30]=1
Reactant: Cc1nn2cc(CC(=O)O)nc2s1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)ncn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4cn5nc(C)sc5n4)CC3)C2)ncn1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a mixture of 2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane dihydrochloride (3-1g, 800 g, 1.87 mol), (2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetic acid (SM-1ae, 406.4 g, 2.06 mol), and triethylamine (1.31 L, 9.37 mol) in dichloromethane (8 L) was added T3P (2150 g, 3.37 mol) dropwise over 45 min and stirred for 1 h maintaining a temperature between 20 and 30° C. Water was added dropwise (4 L) and the reaction was stirred at 30° C. for 15 min. The layers were separated and the aqueous layer was concentrated to remove residual solvent under partial vacuum at 20° C. The aqueous layer was treated with activated charcoal (20 wt %), stirred for 30 min and filtered through Celite® washing with water. The filtrate was adjusted to pH 7.5-8.0 with 1N NaOH. The resulting slurry was extracted with dichloromethane (12 L) and stirred for 10 min at room temperature. The layers were separated and the organic layer was concentrated under reduced pressure to approximately 4 L. Isopropyl acetate (12 L) was added and the solution was concentrated under reduced pressure at 78° C. to 8 L. The solution was cooled slowly over 4 hours to 20° C. The resulting slurry was stirred for 1 h, filtered and washed with isopropyl acetate (2.4 L). The resulting solid was further dried under vacuum at 45° C. for 8 hours to give the title compound 3Z as a white crystalline solid (883 g, 92%). MS (ES+) 514.0 (M+H)+. 1H NMR (CDCl3) δ 1.69-1.72 (m, 4H), 1.88-1.96 (m, 1H), 2.11-2.22 (m, 1H), 2.57 (s, 3H), 2.66 (s, 3H), 2.82-2.88 (m, 1H), 3.03-3.20 (m, 5H), 3.49-3.55 (m, 4H), 3.77 (s, 2H), 3.93-3.97 (m, 1H), 7.36 (d, 1H), 7.53 (s, 1H), 7.61 (s, 1H), 7.84 (d, 1H), 7.93 (s, 1H), 9.10 (s, 1H).
Reaction SMILES: NC(CCC)C#N.[NH2:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:10]#[N:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:12]1([CH:9]([NH2:8])[CH2:10][NH2:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CC(N)c1ccccc1
Agent: CCCC(N)C#N
Agent: [Al+3]
Agent: [H-]
Product: NCC(N)c1ccccc1
Yield: 35 %

Procedure:
Following the procedure as described in Preparation 11, making variations as required to replace 2-aminopentanenitrile with 2-amino-2-phenylacetonitrile, (Crossley et al., J. Chem., Perkin Trans. 1, (1974), 2327-2330) to react with lithium aluminum hydride, 1-phenylethane-1,2-diamine was obtained as a colorless solid in 35% yield. The crude product was used for the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].COC1C(OC)=NS(=O)(=O)N=1.CO[C:24]1[C:28]([NH:29][CH2:30]CSCC2SC=CN=2)=[N:27][S:26](=[O:40])(=[O:39])[N:25]=1.CN>>[CH3:30][NH:29][C:28]1[C:24]([NH:10][CH2:9][CH2:8][S:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[N:25][S:26](=[O:40])(=[O:39])[N:27]=1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nccs1
Reactant: NCCSCc1nccs1
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nccs1

Procedure:
When a methanolic solution of 2-[(thiazol-2-yl)methylthio]ethylamine [prepared according to the procedure described in U.S. Pat. No. 3,950,333] is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and the resultant 3-methoxy-4-{2-[(thiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide treated with methylamine according to the general procedure described in Example 31, the title compound is thereby produced.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([CH2:48][S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)Cc3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.184 g, 0.399 mmol) was dissolved in dichloromethane (3.6 mL), and the solution was treated with triethylamine (0.250 mL, 1.79 mmol) and a-toluenesulfonyl chloride (0.152 g, 0.797 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(a-toluenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0908 g, yield 37%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH:35]O.Cl>O.C(#N)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:35])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH3:34])[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: OO
Reactant: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C=O)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.7 g (14.7 mmol) of NaClO2X4H2O (79% purity) in 7 ml of water is added dropwise to a stirred mixture of 4′-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)methyl]-biphenyl-2-carboxaldehyde (2.5 g, 4.5 mmol) in 10 ml of acetonitrile, 0.16 g of NaH2PO4 in 2 ml of H2O and 2.5 ml of 30% H2O2 at the temperature 10° C. pH of the mixture is adjusted to pH=2 with concentrated HCl and stirring is continued for 1.5 h at room temperature. Reaction mixture is poured into 120 ml of water, stirred for 15 minutes, filtered, washed with 2×10 ml of water and dried in vacuo. Yield: 2.34 g (90.6%)
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[N:4][C:3]=1[C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][N:6]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[C:3]([C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=2)[N:4]=[CH:5]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccnc(-c2ncn(CCc3ccccc3Cl)c2Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ccnc(-c2ncn(CCc3ccccc3Cl)c2-c2ccc(F)cc2)c1
Yield: 48 %

Procedure:
A mixture of 2-[5-bromo-1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]pyridine-4-carbonitrile (1 eq), 4-fluorophenylboronic acid, Pd(dppf)Cl2 (0.1 eq) and Na2CO3 (2 eq, 2 M) in dioxane was refluxed overnight under N2. The reaction mixture was concentrated and purified by FCC (DCM/MeOH=20/1) to give the title compound (48%). [M+H] Calc'd for C23H16ClFN4, 403. Found, 403.