Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[CH3:27])#[N:25].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23]4)=[O:20])[N:17]=3)[N:14]=2)[CH:3]=1)=[O:33])([CH3:28])[CH3:27])#[N:25]
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 50.6 %

Procedure:
Using N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (140 mg, 0.430 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (97 mg, 0.516 mmol), oxalyl chloride (75 μL, 0.860 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (108 mg, 51%) was obtained as a white powder.
Reaction SMILES: [H-].[Na+].C(O[CH:6]([O:10]CC)[N:7]([CH3:9])C)C.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:29]([CH:31]([C:35]1[CH2:40][CH2:39][CH2:38][C:37](=[O:41])[CH:36]=1)C(N)=O)#[N:30]>>[O:10]=[C:6]1[C:31]([C:29]#[N:30])=[C:35]2[C:36]([C:37](=[O:41])[CH2:38][CH2:39][CH2:40]2)=[CH:9][NH:7]1
Reactant: CCOC(OCC)N(C)C
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2

Procedure:
The novel compounds of the present invention originate from a novel process which utilizes dihydroresorcinol as the starting material. That substance thus is allowed to react with a chlorinating reagent such as phosphorus trichloride to afford 3-chloro-2-cyclohexen-1-one. Reaction with cycnoacetamide and sodium hydride results in α-cyano-3-oxo-1-cyclohexen-1-acetamide, which is contacted with a dialkylformamide acetal, for example dimethylformamide diethyl acetal or dimethylformamide dineopentyl acetal, to produce 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile. Elimination of the cyano group is effected by heating with hydrobromic acid, thus affording 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. Heating with an alkyl or cycloalkyl halide produces the corresponding 6-alkoxy and 6-cycloalkoxy 7-aza-1-tetralones together with the N-alkylated or N-cycloalkylated derivatives. Typically, 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione is heated in benzene at the reflux temperature with methyl iodide and silver carbonate to yield 7-aza-6-methoxy-1-tetralone together with 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]([CH3:19])[C:12]3[NH:13][C:14]([CH3:16])=[N:15][C:11]=3[CH:10]=2)[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3[CH:31]=[N:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=4[C:29]=3[NH:28][C:27]2=[O:39])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:16][C:14]1[NH:13][C:12]2[C:17]([CH3:19])=[CH:18][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([N:20]4[CH2:21][CH2:22][CH:23]([N:26]5[C:30]6[CH:31]=[N:32][C:33]7[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=7[C:29]=6[NH:28][C:27]5=[O:39])[CH2:24][CH2:25]4)[CH:3]=3)=[CH:10][C:11]=2[N:15]=1
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1
Reactant: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc2cc(Nc3cc(N4CCC(n5c(=O)[nH]c6c7ccccc7ncc65)CC4)ncn3)cc(C)c2[nH]1

Procedure:
150 mg (0.548 mmol) (6-chloro-pyrimidin-4-yl)-(2,7-dimethyl-1H-benzimidazol-5-yl)-amine, 150 mg (0.559 mmol) 3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one and 1.00 mL (5.81 mmol) DIPEA were refluxed in 1.0 mL DMF. After the reaction had ended the reaction mixture was diluted with MeOH and purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[C:21]([O:30][CH3:31])=[CH:22][C:23]([CH3:29])=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:24]2[CH:25]=[C:20]([F:19])[C:21]([O:30][CH3:31])=[CH:22][C:23]=2[CH3:29])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: COc1cc(C)c(B(O)O)cc1F
Product: COc1cc(C)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1F
Yield: 83 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (1.0 g, 3.78 mmol) and 5-fluoro-4-methoxy-2-methyl-phenylboronic acid (prepared substantially as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503, which is incorporated herein by reference) (1.2 mg, 5.67 mmol) were treated substantially as described in Part A of Example 19a to give 1.15 g (83%) of 2-benzyloxy-4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine: MS (EI) m/z 369.3 [(M+H)+, 100].
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:17][C:16]=2[CH3:27])=[CH:9][C:8]=1[CH3:28])C.[Li+].[OH-]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[S:19][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:29][CH2:30][CH3:31])[C:4]([OH:32])=[O:3])=[C:8]([CH3:28])[CH:9]=2)=[C:16]([CH3:27])[N:17]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccccc3Cl)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3ccccc3Cl)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(2-chloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(2-chloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless oil.
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[CH:33]1([CH2:36][O:37][C:38]2[CH:63]=[CH:62][C:41]([C:42]([NH:44]/[C:45](/[C:56]([NH:58][CH2:59][CH2:60][OH:61])=[O:57])=[CH:46]\[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH3:55])=[CH:49][CH:48]=3)=[O:43])=[CH:40][CH:39]=2)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][O:37][C:38]2[CH:63]=[CH:62][C:41]([C:42]([NH:44][CH:45]([CH2:46][C:47]3[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH3:55])=[CH:51][CH:52]=3)[C:56]([NH:58][CH2:59][CH2:60][OH:61])=[O:57])=[O:43])=[CH:40][CH:39]=2)[CH2:35][CH2:34]1
Reactant: CCOc1ccc(/C=C(\NC(=O)c2ccc(OCC3CC3)cc2)C(=O)NCCO)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: CCOc1ccc(CC(NC(=O)c2ccc(OCC3CC3)cc2)C(=O)NCCO)cc1
Yield: 16 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using 4-(cyclopropylmethoxy)-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (255 mg) to give 41 mg of the title compound (white powder).
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].[BH4-].[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.CS(C)=O>[N+:16]([CH2:19][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:13][CH:12]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(Sc2ccccc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Sc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 30.1 %

Procedure:
To an acetic acid (10 mL) solution of 6-phenylsulfanyl-pyridine-3-carbaldehyde (583 mg, 2.71 mmol) described in Manufacturing Example 97-1-2 were added nitromethane (734 μL, 13.6 mmol) and ammonium acetate (418 mg, 5.42 mmol), and which was stirred for 4 hours 35 minutes at 100° C. under nitrogen atmosphere. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a dimethyl sulfoxide (10 mL) and acetic acid (1 mL) solution of the residue was added sodium borohydride (205 mg, 5.42 mmol), which was stirred for 55 minutes at room temperature. Sodium hydrogencarbonate and water were added to the reaction mixture at room temperature while cooling appropriately, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (212 mg, 30%).