Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:17]2[NH:11][C:12](=[O:13])[NH:14][C:15]2=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1CNC(=O)N1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(C=C2NC(=O)NC2=O)cc1

Procedure:
36.7 g (0.28 mol) of 4-cyanobenzaldehyde, 10 g (0.1 mol) of hydantoin, 21.6 g (0.263 mol) of sodium acetate and 28.6 ml (0.3 mol) of acetic anhydride are heated under reflux in 85 ml of acetic acid for 4 hours. After cooling, the mixture is poured onto ice and extracted with methylene chloride. The methylene chloride phase is concentrated, and the residue is stirred with methanol and filtered off with suction.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[C:15]1([NH:21][C:22](=[O:25])[NH:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([NH:21][C:22](=[O:25])[NH:23][N:24]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1ccccc1
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1

Procedure:
ninhydrin, 4-phenyl semicarbazide hydrochloride.
Reaction SMILES: O[CH:2](O)[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[CH3:17][C:18]([CH3:28])([NH2:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C.CN(C)C=O>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:2][NH:27][C:18]([CH3:28])([CH3:17])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCc2cc(C(=O)C(O)O)ccc2N1
Reactant: CC(C)(N)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(CCc1ccccc1)NCC(O)c1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.4 g (0.006 mole) of 3,4-dihydro-6-(alpha,alpha-dihydroxy-acetyl)-quinolin-2-(1H)-one and 1.37 g (0.008 mole) of 1,1-dimethyl-3-phenyl-propanamine in 60 ml of ethanol and 30 ml of dimethylformamide is heated to 80° C. for 2 hours and, after cooling to room temperature, about 1.5 g of sodium borohydride are gradually added. After 2 hours, the mixture is acidified with acetic acid and the solvent is evaporated off in vacuo. After being rendered alkaline with 2N sodium hydroxide solution, the residue is extracted with methylene chloride. The residue of the organic phase is purified by column chromatography on silica gel (CHCl3 /MeOH 93/7).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:11][CH:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:13](=[O:14])[CH:12]([Cl:11])[CH3:16])=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1N
Reactant: CC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cscc1NC(=O)C(C)Cl
Temperature: -15 °C
Yield: 82 %

Procedure:
To a suspension of 4-amino-thiophene-3-carboxylic acid methyl ester (2.0g) in dichloromethane (25 mL) was added 2-chloropropionyl chloride (1.13 mL). The reaction mixture was then cooled down to −15° C. and a solution of triethylamine (3.2 mL) in dichloromethane (5 mL) was slowly added over 30 minutes. After such time the reaction mixture was allowed to warm up to room temperature, and the solution was washed twice with water, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a light yellow solid (2.1g, 82%). MS (EI): 247.0.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[Br:27][C:28]1[NH:32][N:31]=[C:30]([N+:33]([O-:35])=[O:34])[N:29]=1>C(#N)C.O>[Br:27][C:28]1[N:32]([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[N:31]=[C:30]([N+:33]([O-:35])=[O:34])[N:29]=1
Reactant: O=[N+]([O-])c1n[nH]c(Br)n1
Reactant: CC(C)(C)[Si](C)(C)OCCC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(c1ccccc1)n1nc([N+](=O)[O-])nc1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of (3-bromo-3-phenylpropoxy)(tert-butyl)dimethylsilane (934 mg, 2.84 mmol) in acetonitrile (27 mL) was stirred at room temperature under an atmosphere of nitrogen with sodium iodide (425 mg, 2.84 mmol) for 15 minutes. Potassium carbonate (560 mg, 4.05 mmol) was added and the reaction was heated 60° C. At this temperature 5-bromo-3-nitro-1H-1,2,4-triazole (532 mg, 2.7 mmol) dissolved in acetonitrile (5.3 mL) was added within 30 minutes. The reaction was stirred for 2 hours at 85° C. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a colorless viscous oil (510 mg, 42%) after column chromatography on silica gel using a gradient from heptane to heptane/ethyl acetate 4:1 (v/v) as eluent. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.42-7.36 (m, 5H), 5.91 (dd, 1H), 3.58 (m, 1H), 3.48 (m, 1H), 2.72 (m, 1H), 2.39 (m, 1H), 0.91 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7](=[NH:8])[O:13][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(C)cc1

Procedure:
Ethyl 4-methylbenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, p-tolunitrile (25.6 g, 0.219 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 42.3 g (97%) of the target compound as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][NH:11][C:9]=2[N:10]=1)[CH2:2][CH3:3].[H-].[Na+].[C:30](Cl)(=[O:32])[CH3:31]>C(#N)C.O>[C:30]([N:11]1[C:9]2[N:10]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])[N:6]([CH3:24])[C:7](=[O:23])[C:8]=2[C:13]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[CH:12]1)(=[O:32])[CH3:31]
Reactant: CCCN(CCC)c1nc2[nH]cc(-c3c(C)cc(C)cc3C)c2c(=O)n1C
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C(C)=O)c(=O)n1C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A solution of 2-(dipropylamino)-5-mesityl-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (20 mg, 0.054 mmol) in acetonitrile (1.5 ml) was added sodium hydride (60% in oil, 5 mg, 0.125 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of acetylchloride (20 mg, 0.25 mmol) and acetonitrile (0.5 ml) at 0° C. and stirred for 0.5 hour. After stirring at 80° C. for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 17 mg (77%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][CH:7]=1.Cl[CH:16](OCC)[CH2:17]CCl.ClCCl>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:14][CH:16]=[CH:17][N:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(Cl)CCCl
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Solvent: CCO
Solvent: ClCCl
Product: ClCCCOc1ccc(-c2nccs2)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
A solution of 4-(3-chloropropoxy)benzenecarbothioamide ax71 (0.3 g, 1 eq, 1.31 mmol) in ethyl alcohol (5 ml) is treated with 1,3-dichloro-1-ethoxy-propane (0.4 ml, 2.7 eq, 3.6 mmol) and the mixture is stirred at 110° C. during 4 h. The mixture is then poured into dichloromethane (10 ml) and is washed with water. The organic phase is dried over magnesium sulfate and concentrated. Purification by chromatography over silicagel (eluent: dichloromethane) affords 120 mg of 2-[4-(3-chloropropoxy)phenyl]-1,3-thiazole i88.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4]([CH:5]=O)[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8].[C:12](O)(=O)[CH2:13][C:14]([OH:16])=[O:15].CCCCCC>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:11])[C@@H:4](/[CH:5]=[C:13](/[C:14]([OH:16])=[O:15])\[CH3:12])[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@H]1[C@H](C=O)C1(C)C
Reactant: O=C(O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@H]1[C@H](/C=C(\C)C(=O)O)C1(C)C
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 0.666 g of methyl (±)-trans-2,2-dimethyl-3-formylcyclopropanecarboxylate was dissolved in 10 mL of a designated solvent. A designated amount of an amine and 1.000 g of malonic acid was then added thereto, and the resulting mixture was stirred under heating. After the mixture was allowed to cool to room temperature, 50 mL of ethyl acetate was added to said mixture and the resulting mixture was washed with 3N-hydrochloric acid and then saturated brine to obtain an organic layer therefrom. The organic layer was dried over anhydrous magnesium sulfate and thereafter evaporated under reduced pressure in order to produce a residue. The residue was subjected to silica gel chromatography, wherein the eluent was a mixture of n-hexane and ethyl acetate at a volume to volume ratio of 3:1. Methyl(±)-trans-2,2-dimethyl-3-{2-carboxy-(E)-1-propenyl}cyclopropanecarboxylate was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C@@:11]([CH3:27])([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:12]([C:15](OCC)=[O:16])([F:14])[F:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C@@:11]([CH3:27])([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:12]([F:13])([F:14])[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)[C@@H]1C[C@H]1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1[C@@](C)(N[S@](=O)C(C)(C)C)C(F)(F)CO
Yield: 81 %

Procedure:
Starting from (1R,2R)-2-[(R)-2-ethoxycarbonyl-2,2-difluoro-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-ethyl]-cyclopropanecarboxylic acid tert-butylester (intermediate J3.2) the reduction with lithium borohydride yielded the (1R,2R)-2-[(R)-2,2-difluoro-3-hydroxy-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-propyl]-cyclopropanecarboxylic acid tert-butyl ester (81% yield) as a colorless oil. MS (ISP): m/z=370.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17]C(=O)C)[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].[OH-].[Na+].Cl>CO>[NH2:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[C:3]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)(=[O:23])=[O:24])[C:2]([Cl:1])=[N:7][CH:6]=3)=[N:13][N:12]2[CH:14]=1
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)ccc2n1
Temperature: 0 °C
Yield: 14.7 %

Procedure:
A 100 mL, round-bottomed flask was charged with N-(6-(6-chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (150 mg, Example 12) and methanol (10 mL)-NaOH (10 N, 5 mL). The mixture was refluxed for 2 h. After the solution was cooled to 0° C., 10 N HCl was added until pH=7. The crude product was concentrated in vacuo. Purification by silica gel chromatography (10 to 50% MeOH/CH2Cl2), followed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 40 to 90% CH3CN/H2O, 0.1% TFA, over 15 min) (Phenomenex, Torrance, Calif.) provided N-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (20 mg, 5.0% yield) as a yellow solid. MS (ESI positive ion) m/z: 419 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.28 (t, J=8.80 Hz, 1H), 7.22-7.31 (m, 1H), 7.49 (s, 1H), 7.55 (d, J=9.19 Hz, 1H), 7.70-7.77 (m, 1H), 7.82-7.90 (m, 2H), 8.52 (d, J=2.15 Hz, 1H), 8.72 (d, J=2.15 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[O:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[C:23]([CH2:27][NH2:28])[CH:24]=[CH:25][CH:26]=2)[CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:28][CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:17]4[CH2:18][CH2:19][O:14][CH2:15][CH2:16]4)[CH:22]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cccc(CN2CCOCC2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(CN4CCOCC4)c3)ccc12
Yield: 18.9 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), [3-(morpholinomethyl)phenyl]methylamine (131 mg, 0.636 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-morpholin-4-ylmethyl-benzylamino)-2H-phthalazin-1-one (42 mg) as an off white solid, 1H (400 MHz, d6-DMSO) δ: 2.11 (m, 4H), 3.23 (s, 2H), 3.30 (t, 4H), 4.25 (d, 2H), 6.60 (s, 1H), 6.98 (m, 2H), 7.10 (m, 3H), 7.50 (t, 1H), 7.74 (d, 1H), 12.16 (s, 1H) ppm; m/z (M+1) 384.94.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([N:22]([CH2:24][CH3:25])[CH3:23])=[O:21])=[CH:18][CH:17]=1>>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[C:2]([NH:12][C:13]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:14]=2[O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([N:22]([CH2:24][CH3:25])[CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: Clc1ccnc2ncccc12
Product: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (100 mg, 0.61 mmol) was reacted with the product from Example 133b (185 mg, 0.61 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (141 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.86-1.18 (m, 3 H) 2.62-2.92 (m, 5 H) 6.76 (d, J=7.35 Hz, 1 H) 6.94 (d, J=8.82 Hz, 2 H) 7.25 (d, J=8.09 Hz, 2 H) 7.34 (d, J=8.82 Hz, 1 H) 7.63 (dd, J=8.82, 2.57 Hz, 1 H) 7.75 (d, J=2.57 Hz, 1 H) 7.85 (dd, J=8.46, 4.41 Hz, 1H) 8.61 (d, J=6.99 Hz, 1 H) 8.96 (dd, J=8.64, 1.29 Hz, 1 H) 9.14 (dd, J=4.23, 1.29 Hz, 1 H) 11.06 (s, 1 H) 14.74 (s, 1 H); MS (ESI+) m/z 433 (M+H−TFA)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:15][O:16][CH2:17][C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)=[O:19]
Reactant: COCC(=O)O
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(NC(=O)COC)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-aminocinnamate (2.00 g) and methoxyacetic acid (1.04 ml) in N,N-dimethylformamide (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.61 g) and 1-hydroxybenzotriazole (2.12 g) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give ethyl 4-(methoxyacetamido)cinnamate (2.34 g) as a pale yellow powder.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](O)=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-phenyl-5-carboxypyridine (520 mg, 2.61 mmol) in tetrahydrofuran (10 mL) at 0° C. was added 1.0M lithium aluminum hydride in tetrahydrofuran (2.61 mL, 2.61 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 16 hours, cooled to 0° C., and quenched by dropwise addition of water (0.20 mL), 4N aq. NaOH (0.20 mL), and water (0.60 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (silica gel, 0-5% MeOH in CH2Cl2) to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2([C:12]3[CH:24]=[CH:23][C:15]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2([C:12]3[CH:24]=[CH:23][C:15]([N:16]([C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[CH3:28])=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(C2(C(=O)c3cccnc3)CC2)cc1[N+](=O)[O-])C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(=O)C(F)(F)F)c1ccc(C2(C(=O)c3cccnc3)CC2)cc1[N+](=O)[O-]

Procedure:
1.15 g (3.0 mmol) of 4-[1-[(pyridin-3-yl)-carbonyl]cyclopropyl]-2-nitro-trifluoroacetylaniline are dissolved in 50 ml acetone and after the addition of 2.0 g potassium carbonate and 0.8 ml methyl iodide refluxed for two hours. The insoluble matter is filtered off and the solution is evaporated down. The residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate (1:1 and 1:4).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:9][CH2:10][C:11](OC)=[O:12].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:9][CH2:10][CH2:11][OH:12]
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=CCCO)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Under a nitrogen atmosphere, 12.4 g (0.326 mol) of lithium aluminum hydride was added little by little to a solution of 35 g (0.13 mol) of methyl 4,8,12-trimethyltridec-3-enoate in dry tetrahydrofuran (320 mL) at 0° C. After being stirred at 50° C. for 2 hours, the reaction mixture was cooled on ice, followed by careful addition of saturated sodium sulfate aqueous solution until the resulting gray suspension turned white. Sodium sulfate was added to the solution at room temperature for drying. After filtration, the filtrate was concentrated to obtain 31 g of the title compound (99% yield) as a colorless transparent liquid. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[C:19](Br)=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Li])CCC.CI.CO>CCOCC.CCCCCC.O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[C:19]([CH3:21])=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Brc1cc2c(cc1CCOCc1ccccc1)OCO2
Solvent: O
Solvent: CCOCC
Solvent: CI
Product: Cc1cc2c(cc1CCOCc1ccccc1)OCO2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
3.0 g of 5-(2-benzyloxyethyl)-6-bromo-1,3-benzodioxole was dissolved in 100 m(of anhydrous ether. 8.5 ml of a 1.6 M solution of n-butyllithium in hexane was added to the solution at -78° C. and the reaction was conducted at -50° C. for 2 h. The reaction mixture was cooled again to -78° C. 6.4 g of methyl iodide was added thereto and the temperature was gradually elevated to room temperature. Methanol and water were added to the reaction mixture. After extraction with ethyl acetate, the extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude methyl compound. After purification according to silica gel column chromatography (ethyl acetate/ hexane=2:98), 1.9 g of the intended compound was obtained in the form of a pale yellow oil.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.C([NH:38][C@H:39]([C:41](O)=[O:42])[CH3:40])(OC(C)(C)C)=O>>[NH2:38][C@@H:39]([CH3:40])[C:41]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:22]2[S:23][C:9]3[C:8]([N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[N:13][C:12]([C:14]4[CH:19]=[N:18][C:17]([NH2:20])=[N:16][CH:15]=4)=[N:11][C:10]=3[CH:21]=2)[CH2:30][CH2:29]1)=[O:42]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Agent: Cl
Product: C[C@H](N)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with Boc-alanine via General Procedure B followed by Boc removal with TFA to generate 30.9 mg of 104 after purification. MS (Q1) 484.3 (M)+.