Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cc(CCl)ccc1O
Solvent: CC(=O)O
Product: O=Cc1cc(CCl)cc([N+](=O)[O-])c1O
Temperature: 30 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
1.79 g. (0.01 mole) of 5-chloromethylsalicylaldehyde, prepared according to Angyal, S. J. et al., J. Chem. Soc. 1950, 2145, was dissolved in 20 ml. of glacial acetic acid. To this solution there was added a solution of 0.63 g. fuming nitric acid in 10 ml. glacial acetic acid over 30 minutes, keeping the mixture at 30° C., followed by stirring at 30° C. for 2 hours. The solution was then poured over ice to give a precipitate which was crystallized from methylene chloride giving the title product. Another crop was obtained by extraction of the aqueoue phase, drying with anhydrous sodium sulfate, evaporation and crystallization from methylene chloride. Total yield: 53%.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>C1(C)C(C)=CC=CC=1>[Cl:12][C:6]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)Nc1c(Cl)cncc1Cl
Reactant: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1c(Cl)cncc1N1CCNCC1

Procedure:
A mixture of 3,5-dichloro-4-(1-methylethyl)aminopyridine (PREPARATION 41, 1.77 g) and piperazine (2.96 g) in xylene (18 ml) is refluxed for 40 hr. The mixture is cooled and then treated with concentrated hydrochloric acid (8 ml). After further cooling, a precipitate forms and the organic liquid is separated. The aqueous phase is diluted with an excess of a solution of aqueous sodium hydroxide (10%) and then is extracted with chloroform (3×). The combined organic extracts are washed with water, then saline, dried over sodium sulfate, and concentrated to an oil. The crude product is flash chromatographed on silica gel eluting with methanol. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.20, 3.04, 3.18, 4.46, 4.73 and 8.50δ; CMR (CDCl3) 24.0, 44.3, 45.9, 50.2, 118.2, 135.8, 148.3 and 155.4 δ.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[N:17][C:18]([C:22]#[N:23])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(NC2CCN(Cc3ccccc3)CC2)nn1
Temperature: 160 °C
Yield: 36 %

Procedure:
A mixture of (1-benzyl-piperidin-4-yl)-(6-chloro-pyridazin-3-yl)-amine (D1) (3 g, 9.9 mmol), zinc cyanide (2.09 g, 17.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.74 g, 2.3 mmol) in N,N-dimethylformamide (30 ml) was heated at 160° C. for 30 min., under microwave irradiation (Milestone MW-oven). The solvent was then evaporated in vacuo and an aqueous solution of potassium carbonate (10%) and ethyl acetate were added. The organic phase was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; 0 to 1.5% ammonia in methanol (7M)/dichloromethane) and then by HPLC to yield D2 (1.06 g, 36%) as a solid. C17H19N5 requires 293. Found 294 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]([CH3:26])([CH3:25])[C@H:9]2[NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([Cl:24])=[CH:19][CH:18]=3)=[O:14])=[CH:5][CH:4]=1)#[N:2].[C:27](C1C=C2C(CC(C)(C)C2NC(C2NC3C(C=2)=CC(Cl)=CC=3)=O)=CC=1)#N.C([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:27])[C:15]([C:13]([NH:12][C@H:9]1[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH2:7][C:8]1([CH3:26])[CH3:25])=[O:14])=[CH:23]2
Reactant: CC1(C)Cc2ccc(C#N)cc2C1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N[C@H]2c3cc(C#N)ccc3CC2(C)C)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Example 2 N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-chloro-1H-indole-2-carboxamide (30 mg, 0.083 mmol) and K2CO3 (34 mg, 2.48 mmol) in DMF (0.3 mL) was added methyl iodide (6 μL, 0.091 mmol) and the resulting mixture was stirred at rt for 16 h. Water (˜5 mL) was added dropwise followed by stirring for an additional 30 min. The precipitated solid was collected by vacuum filtration, rinsed with additional water (˜5 mL) and dried in vacuo to afford the title product as a white solid (26 mg). HPLC Ret. time: 3.79 min. LCMS MH+ (m/z) 378.30. 1H NMR: (DMSO-d6, 400 MHz): 8.72 (d, 1H), 7.71 (s, 1H), 7.68 (d, 1H), 7.65 (s, 1H), 7.58 (d, 1 H), 7.44 (d, 1 H), 7.26 (dd, 1 H), 7.18 (s, 1H), 5.34 (d, 1H), 4.00 (s, 3H), 2.52-2.48 (m, 2 H), 1.21 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([OH:17])[C:6]=12.Br[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:21]3)[C:6]=12
Reactant: Cn1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC(CBr)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCC3CCCN(C(=O)OC(C)(C)C)C3)c3c(Br)cnn3c2)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (60.0 mg, 0.205 mmol), tert-butyl 3-(bromomethyl)piperidine-1-carboxylate (114 mg, 0.410 mmol), and NaH (29.5 mg, 0.737 mmol) were suspended in DMF (2 ml), then heated to 60° C. After 2 h, the reaction mixture was quenched with 1 ml of saturated aqueous ammonium chloride, diluted in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine. The combined aqueous layers were extracted with ethyl acetate (1×30 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) afford a yellow oil. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate, filtered and concentrated to afford tert-butyl 3-({[3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy}methyl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>CC(O)=O.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1Cl
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
4-Amino-2-(2-chloro-phenylamino)-3-fluoro-5-nitro-benzoic acid methyl ester 5b (0.30 g, 0.88 mmol) is suspended in AcOH (5 mL) and zinc dust (0.29 g, 4.42 mmol) is added. After 15 minutes, the reaction is complete. The reaction mixture is diluted with ethyl acetate and filtered through Celite. The filtrate is washed with water, saturated NaHCO3, 10% K2CO3 and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 0.13 g (48%) pure desired product as a whitish brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:27][O:28][NH:29][CH3:30].C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]([O:28][CH3:27])[CH3:30])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a solution of 6-chloro-nicotinic acid (94.5 g, 0.6 mol) in dichloromethane (1000 mL) was added N-methyl morpholine (181.8 g, 1.8 mol) followed by iso-butyl chloroformate (81.9 g, 0.6 mol) at −25° C. under N2 atmosphere. The mixture was stirred for 15 minutes and then O,N-dimethyl hydroxylamine hydrochloride (64.35 g, 0.66 mol) was added. The mixture was stirred for 30 min at −25° C. and warmed to room temperature slowly. The mixture was stirred for an additional hour at room temperature and a saturated solution of NaHCO3 (800 mL) was added. The separated aqueous layer was extracted with dichloromethane (500 mL×3) The combined organic layers were washed with water and brine. The solvent was evaporated to give the crude product, which was purified by column chromatography to give the pure product 6-chloro-N-methoxy-N-methyl-nicotinamide as a white solid (56 g, 46.6%).
Reaction SMILES: [NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([O:28]C)=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:4])=[O:3].CO.[OH-].[Na+].Cl>CO.[H][H]>[NH2:1][S:2]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[CH2:15][N:14]3[C:30]=2[CH:31]=1)=[O:7])(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(N)(=O)=O)cc3n2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(N)(=O)=O)cc21
Temperature: 60 °C
Yield: 93.5 %

Procedure:
Methyl 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (725 mg, 1.39 mmol) was dissolved into MeOH//THF (1:1, 16 mL) and treated with 1M aqueous NaOH (3 mL). The reaction mixture was stirred and heated at 60° C. for 0.5 h and cooled to rt. The reaction solution was diluted with MeOH/H2 O (2:1, 15 mL), neutralized with 1M aqueous HCl (3 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield 10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (650 g, 1.3 mmol, 92%) as a bright yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.16-2.22 (m, 10H), 2.82-2.96 (m, 1H), 3.94 (s, 3H), 4.07-4.29 (m, 1H), 5.57-5.80 (m, 1H), 7.14-7.23 (m, 2H), 7.55-7.63 (m, 2H), 7.88-7.94 (m 2H), 8.18 (s, 1H). LCMS: m/e 510 (M+H)+, ret time 2.85 min, column B, 4 minute gradient.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:29]>CO>[ClH:29].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Yield: 67.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3′-cyano-3-biphenylyl)methylidene]-1-piperidinecarboxylate (1.87 g, 4.99 mmol) in MeOH (499 mL) was added HCl (4.99 mL, 1N, 4.99 mmol) then was applied to H-cube hydrogenation apparatus until the reaction was complete per monitoring with LC-MS. The reaction mixture was concentrated to afford 1.40 g (67%) of the title compound. LC-MS m/z 381 (M+H)+.