Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[Cl:17])[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Clc1ccc(N2CCNCC2)cc1Cl
Yield: 27.7 %

Procedure:
This compound was prepared according to the procedure of Preparation 1. A mixture of 44.6 g (0.25 mole) of bis(2-chloroethyl)amine hydrochloride, 40.5 g (0.25 mole) of 3,4-dichloroaniline and 50.0 g (0.36 mole) of potassium carbonate in a total volume of 500 ml of n-butanol gave an oil as residue. Trituration of the oil with petroleum ether (30°-60° C.) gave 16.0 g (28%) of white solid, m.p. 62°-65° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[OH:4].[OH-].[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl.O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:16](=[O:17])[CH2:15][Cl:14])=[CH:6][CH:7]=1
Reactant: NCC(O)c1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.4 %

Procedure:
To a solution of compound 2-amino-1-(4-bromophenyl)ethanol (2.0 g, 10 mmol) in CH2Cl2 (40 mL) and water (40 mL) was added NaOH (0.48 g, 12 mmol) and chloroacetyl chloride (1.7 g, 15 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature and stirred for 6 hours. The layers were separated. The organic was washed with 3% HCl and saturated NaHCO3, dried over sodium sulfate, and concentrated to afford the title compound (2.0 g, 76% yield) as a yellow solid. 1H NMR: (400 MHz, CDCl3): δ 7.45 (d, 2H), 7.19 (d, 2H), 6.98 (br. s, 1H), 4.80 (m, 1H), 4.01 (s, 2H), 3.68 (m, 1H), 3.30 (m, 1H), 2.82 (br. s, 1H):
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[CH2:10][C:11](=O)[CH2:12][CH3:13]>C(O)CC>[CH2:12]([C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][N:3]2[CH:10]=1)[CH3:13]
Reactant: CCC(=O)CBr
Reactant: Cc1ccc(N)nn1
Solvent: CCCO
Product: CCc1cn2nc(C)ccc2n1
Temperature: 25 °C

Procedure:
3-Amino-6-methylpyridazine (4.00 g, 27.5 mmol) and 1-bromo-2-butanone (90%, 7.38 g, 44.0 mmol) were heated in 1-propanol (40.0 ml) for 13 hours under reflux. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and then the residues were dissolved in acetone (50.0 ml) and neutralized with 20% aqueous sodium hydroxide solution. The reaction solution was concentrated under reduced pressure, and then the residues were dissolved in chloroform, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (isopropanol:hexane=1:2), to give the title compound as gray crystals. The yield was 2.33 g (39.4%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[S:8][C:9]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][C:14]([N+:20]([O-])=O)=[CH:15][CH:16]=4)[C:10]=3[N:11]=2)[N:3]=[CH:2]1.CO.[H][H]>[Ni].O1CCOCC1>[NH2:20][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][C:9]3[S:8][C:7]([CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)=[N:11][C:10]=32)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2
Yield: 57 %

Procedure:
5.0 g of Raney nickel (wet) was added to a solution of 0.52 g of.2-(4-imidazolylmethyl)-8-nitro-4,5-dihydronaphtho[1,2-d]thiazole obtained in Example 23 in 1,4-dioxane (40 ml)-methanol (20 ml), and the mixture was stirred for 2 hours in an atmosphere of hydrogen (1 atm). After filtration of insoluble matter, the solvent was evaporated from the filtrate, and the residue was mixed with ethyl acetate to effect crystallization. The resultant crude crystals were washed with hot ethyl acetate to afford 0.27 g (57%) of 8-amino-2-(4-imidazolylmethyl)-4,5-dihydronaphtho[1,2-d]thiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[N+:12]([O-])(O)=O>[Pd].CO>[NH2:12][C:3]1[C:2]([CH3:1])=[CH:11][C:6]2[NH:7][C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2oc(=O)[nH]c2c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2[nH]c(=O)oc2cc1N
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
5-Methyl-3H-benzoxazol-2-one (1.10 g, 7.38 mmol) added to stirring Nitric acid (6.00 mL, 143 mmol). After stirring 1 h, the mixture was heated at 50° C. for 4 h, cooled and then poured into 100 mL ice and allowed to stand overnight to melt. The yellow solids were collected by filtration, washing with water. The crude nitro product was hydrogenated (25 psi) over 10% Palladium on Carbon (50% Wet) (0.240 g, 0.113 mmol) in Methanol (30.0 mL) for 3 h. The mixture was filtered through Celite and rinsed with MeOH (50 mL). After conc. in vacuo, 6-Amino-5-methyl-3H-benzoxazol-2-one (0.765 g; Yield=63.2%) was isolated as an off-white solid.
Reaction SMILES: [C:1]([C:3]1([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[O:25][C:24]=3[C:23]([O:33][CH3:34])=[CH:22][CH:21]=2)[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][N:7]([CH2:13][C:14]([O:16]CC)=[O:15])[C:6](=[O:19])[C:5]=2[CH2:4]1)#[N:2].[OH-].[Na+]>C(O)C.O>[C:1]([C:3]1([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[O:25][C:24]=3[C:23]([O:33][CH3:34])=[CH:22][CH:21]=2)[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][N:7]([CH2:13][C:14]([OH:16])=[O:15])[C:6](=[O:19])[C:5]=2[CH2:4]1)#[N:2]
Reactant: CCOC(=O)Cn1cnc2c(c1=O)CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2(C#N)CCc3ncn(CC(=O)O)c(=O)c3C2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the compound obtained in example 19 (100 mg, 0.2188 mmol) in 4 ml of ethanol was added 1N NaOH solution (3 ml) and the reaction mass was allowed to stir at room temperature for 4 hrs. The reaction mass was diluted with 20 ml water and washed 3 timed with 25 ml diethyl ether. The aqueous layer was acidified with 1N aq. HCl to pH 2-3 and extracted with chloroform. The organic layer was washed with water followed by brine, and concentrated under vacuum. The residue was triturated with ether to give 45 mg (Yields-48%) of product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:33])([CH3:32])[C:13]([N:15]1[CH2:27][C:26](=O)[C:25]2[C:24]3[C:23]([C:29]([O-])=[O:30])=[CH:22][CH:21]=[CH:20][C:19]=3[NH:18][C:17]=2[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.C1C2NC3C=CC=C4C(=O)[NH:51][N:52]=C(C=2C=34)CC1>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]([CH3:33])([CH3:32])[C:13](=[O:14])[N:15]1[CH2:16][C:17]2[NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29](=[O:30])[NH:51][N:52]=[C:26]([C:25]=2[C:24]=34)[CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NN=C2CCCc3[nH]c4cccc1c4c32
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N1CC(=O)c2c([nH]c3cccc(C(=O)[O-])c23)C1
Agent: NN
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
The target product was prepared from 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate according to the procedure similar to that for Compound 1. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.2 (s, 1H), 7.18-7.55 (m, 8H), 4.82-4.91 (m, 4H), 4.43-4.55 (m, 2H), 1.25 (s, 6H). MS (ESI) m/e [M+1]+ 446.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](O)=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35]([NH2:37])[CH3:36]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:30])[NH:37][CH2:35][CH3:36])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: CCNC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and ethylamine gas Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C30H32N4O2
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[Na+].Br[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:17]([OH:19])=[O:18]>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:16]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7])[C:17]([OH:19])=[O:18]
Reactant: O=C(O)C(Br)c1ccccn1
Reactant: O=C(O)COc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1ccccc1OC(C(=O)O)c1ccccn1

Procedure:
A mixture of 2-hydroxyphenoxy acetic acid (16.8 g. 0.1 mole) and 80 ml. of 5N aqueous sodium hydroxide (0.4 mole) is stirred until solution is effected, then the solution treated with 2-bromo-2-(2-pyridyl)-acetic acid (21.6 g. 0.1 mole), and refluxed for 20 hours. The cooled solution is taken to neutrality and the diacid crystallized from benzene to give 2-(2-pyridyl)-2-(carboxymethoxyphenoxy)-acetic acid.
Reaction SMILES: [Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8].C(O)=O.[Cl-].[Na+]>O>[Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=C(Cl)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C=C(Cl)CN(CC=O)C(=O)OCC

Procedure:
151 g (0.6 mol) of ethyl N-(2-chloroallyl)-N -(2,2-dimethoxyethyl)-carbamate are heated under reflux for 3 hours with 60 ml of formic acid in 1.2 1 of water. The mixture is saturated with sodium chloride, and the aqueous phase is separated off and extracted twice with 300 ml of methylene chloride each time. The organic phases are washed with saturated sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:11][CH:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9]2)[CH:3]=1.[CH:16]([Si:19]([C:26]#[CH:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].C(N(CC)CC)C>[Cu](I)I.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>[CH3:15][O:14][CH2:13][CH2:12][CH:10]1[CH2:11][CH:8]([C:4]2[CH:3]=[C:2]([C:27]#[C:26][Si:19]([CH:16]([CH3:18])[CH3:17])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=[CH:6][CH:5]=2)[CH2:9]1
Reactant: COCCC1CC(c2cccc(Br)c2)C1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCCC1CC(c2cccc(C#C[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Yield: 90.3 %

Procedure:
In a CEM snap top microwave vial were combined 1-Bromo-3-[3-(2-methoxy-ethyl)-cyclobutyl]-benzene (0.340 gm 1.28 mmol), triisopropylsilylacetylene (0.29 g, 1.12 mmol), copper iodide (9 mg, 0.178 mmol), tetrakis(triphenylphosphine)palladium (29 mg, 0.088 mmol) and triethylamine (1.30 g, 12.8 mmol). The vial was quickly agitated then irradiated in a CEM Explorer™ microwave instrument for 30 minutes at 80° C. Purification by column chromatography (hexanes) afforded an oil 375 mg (80%). This material was used in next step without further characterization.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[N:3]=1.[NH2:16][NH2:17]>N1C=CC=CC=1>[NH:16]([C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[N:3]=1)[NH2:17]
Reactant: Clc1ncc2c(n1)-c1ccccc1CC2
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ncc2c(n1)-c1ccccc1CC2

Procedure:
Crude 2-chloro-5,6-dihydrobenzo[h]quinazoline was heated at 120° C. in a mixture of anhydrous pyridine (20 mL) and anhydrous hydrazine (7 mL) for 4 h. The solvent was removed under vacuum and the residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-hydrazinyl-5,6-dihydrobenzo[h]quinazoline as a white solid, 2.16 g. 1H NMR (CDCl3, 300 MHz) 8.27 (d, 1H), 8.20 (s, 1H), 7.35 (m, 2H), 7.21 (d, 1H), 6.42 (s, 1H), 4.00 (br s, 2H), 2.91 (m, 2H), 2.80 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz) 164.29, 160.00, 156.72, 139.87, 132.83, 131.02, 128.25, 127.25, 125.47, 119.03, 28.54, 24.24; MS (ES) 213 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C1(C)C=CC=CC=1.[CH2:22]([N:25]([CH2:31][CH:32]=O)[C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:23]=[CH2:24]>O>[CH2:7]([N:6]1[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:24][CH:23]2[CH:32]1[CH2:31][N:25]([C:26]([O:27][CH2:28][CH3:29])=[O:30])[CH2:22]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CC2CN(C(=O)OCC)CC2N1Cc1ccccc1

Procedure:
50 g (0.25 mol) of N-benzylglycine ethyl ester in 1 1 of toluene are heated under reflux in a water separator and 43 g (0.25 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are added dropwise during the course of two hours. The mixture is heated under reflux until water no longer separates and concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.[Br-].[NH4+].CC(C)=[O:16]>O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:16])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: [Br-]
Agent: [NH4+]
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
5.0 g. of Acetonine and 3.2 g. of ammonium bromide were heated at 44°C. for 15 hours in a mixed solvent comprising acetone and water in various ratios as shown hereinbelow to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 5 to obtain triacetonamine in a yield as shown hereinbelow.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:31])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@@H:13]3[C@H:18]([F:31])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COCCO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](F)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile obtained in example 21 (400 mg, 1.14 mmol) in DCM (10 mL) at 0° C. was added DAST (0.18 mL, 1.34 mmol) and stirred at room temperature for 1 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was diluted with DCM, water and extracted, organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 30% EtOAc in Hexane) provided the title compound (215 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[O:18]C)[C:5]([NH2:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.[NH4+].[Cl-]>ClCCl>[NH2:20][C:5]1[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=2[OH:18])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CCCc1ccc(Oc2nc(Cl)ccc2N)c(OC)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCc1ccc(Oc2nc(Cl)ccc2N)c(O)c1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
To a solution of 6-chloro-2-(2-methoxy-4-propyl phenoxy) pyridin-3-amine (0.1 mmol; 30 mg) under argon, in dichloromethane (2 mL), cooled to −78° C., was added BBr3 (0.5 mmol; 0.5 mL) dropwise. The reaction mixture was allowed to stir for 5 hr, with gradual warming to −20° C. At −20° C., the reaction was hydrolysed with saturated NH4Cl (4 mL), extracted with dichoromethane (3*10 mL). Combined organic phases dried over Na2SO4, concentrated in vacuo, to give the desired product as a light brown solid without further purification (27 mg 0.1 mmol; 97%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(Cl)cc3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.18 min; [M+H]+=425.96.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][C:32]=3[C:38]([F:40])([F:39])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(C(F)(F)F)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-fluoro-2 trifluoromethyl-benzaldehyde. MS (ESI) m/z 552.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[NH:22]=[C:23]=N.CN>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:22][CH3:23])=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Reactant: N=C=N
Agent: CN
Solvent: ClCCl
Product: CNC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 23.1 %

Procedure:
A mixture of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropyl-methyl)glycine (0.148 g, 0.5 mmol), and resin bounded carbodiimide (PS-Carbodiimide) (1.0 g, 1.26 mmol/g) was shaken in CH2Cl2 (15 mL) for 30 min, then methylamine (33% solution in water, 0.1 mL, 1 mmol) was added, and the mixture was shaken for another 12 h. The resin was filtered and washed with CH2Cl2 (2×10 mL). The resulting filtrate was concentrated under vacuum. The residue was purified via preparative HPLC to obtain 0.036 g (23%) of the title compound as a white foam: 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=8.5 Hz, 1H), 6.99 (bs, 1H), 6.89 (dd, J=8.8, 2.6 Hz, 1H), 6.28 (bs, 1H), 4.08 (s, 2H), 3.34 (d, J=6.6 Hz, 2H), 2.80 (d, J=4.7 Hz, 3H), 1.06 (m, 1H), 0.65 (m, 2H), 0.31 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9].O.[NH2:20][NH2:21]>C(O)C>[CH2:6]([CH:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:21][NH:20][C:3](=[O:2])[CH2:4]1)[CH2:7][CH2:8][CH3:9]
Reactant: NN
Reactant: CCCCC(CC(=O)OC)C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCC1CC(=O)NN=C1c1ccccc1

Procedure:
A solution of 3-benzoyl-heptanoic acid methyl ester (4.72 g, 19 mmol) and hydrazine monohydrate (4.6 ml, 95 mmol) in ethanol (50 mL) is reflux for 12 hours. The solvent and excess hydrazine monohydrate is removed in vacuo and the residue is partitioned with EtOAc (80 mL) and water (80 mL). The layers are separated and the organic phase is washed with brine (60 mL), dried (Na2SO4) and evaporated in vacuo. Hash column chromatography of the residue (silica gel, 2:1 hexane, EtOAc) provides a creamy solid. LC-MS (M+1) 231. 1H NMR (δ, CDCl3) 8.84 (s, 1H), 7.72-7.79 (m, 2H), 7.37-7.43 (m, 3H), 3.19-3.30 (m, 1H), 2.62 (d, J=6.8 Hz, 2H), 1.52-1.62 (m, 2H), 1.21-1.43 (m, 4H), 0.87 (t, J=7.8 Hz, 3H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: Cc1ccc(CN)cc1
Solvent: CO
Product: Cc1ccc(CN=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Isopropyl N cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and 4-methylbenzylamine (0.35 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.60 g, 2.4 mmol, yield: 91%) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[S:7][C:6]=2[CH:25]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:8]1[S:7][C:6]2[CH:25]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(C)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(C)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 6-methyl-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-aminoanilino)-6-methylbenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[CH2:10][OH:11].FC(F)(F)S(O[C:18]1[C:19]2[CH2:40][N:39]([CH3:41])[CH2:38][CH2:37][C:20]=2[N:21]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][N:33]=[C:32]3[CH3:36])=[CH:27][CH:26]=2)[N:23]=1)(=O)=O>CS(C)=O>[CH3:41][N:39]1[CH2:38][CH2:37][C:20]2[N:21]=[C:22]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH3:36])=[CH:29][CH:30]=3)[N:23]=[C:18]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][C@H:2]3[CH2:10][OH:11])[C:19]=2[CH2:40]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Reactant: OC[C@@H]1Cc2ccccc2N1
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@H]4CO)n2)CN(C)CC3)cc1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
(S)-Indolin-2-ylmethanol (25.5 mg, 0.17 mmol) was added to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (80 mg, 0.17 mmol, Example 9a) in DMSO (1 mL). The reaction was heated to 80° C. for 2 h. The solution was allowed to cool down, filtered and the product was purified on preparative HPLC to give (S)-(1-(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)indolin-2-yl)methanol (22.00 mg, 27.6%). MS (ESI+)/(ESI−) m/z 468/466