Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3](=[CH:18][CH3:19])[CH:4]=[CH:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].O.NN.C(O)C>[OH-].[Na+]>[CH2:18]([C:3](=[CH:1][CH3:2])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:19]
Reactant: CC=C(C=CCN1C(=O)c2ccccc2C1=O)CC
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=C(C=CCN)CC
Yield: 105.6 %

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (5.0 g), hydrazine monohydrate (2.45 g), and ethanol (150 ml) was refluxed for 1.5 hours under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give crude 4-ethyl-2,4-hexadien-1-ylamine (2.59 g) as an oil. The crude oil was dissolved in dichloromethane (30 ml) containing triethylamine (6.28 g). To this solution cooled to 0° C. was added nicotinic acid chloride hydrochloride (3.41 g) in small portions during 10 minutes. After 30 minutes, triethylamine (4.19 g) and nicotinic acid chloride hydrochloride (0.79 g) were added and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (2% methanol-dichloromethane) to give a mixture of N-[(2E,4E) and (2Z,4E)-4-ethyl-2,4-hexadien-1-yl]-3-pyridinecarboxamide (4.6 g) which crystallized on standing.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH:12]([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:3].Cl.Cl.[NH2:17][C:18]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:19]=1[O:20][CH2:21][CH2:22][OH:23].N>O.C(O)C>[ClH:1].[NH2:28][C:26]1[C:25](=[N:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:2][CH3:3])[CH:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=2)[CH:24]=[C:19]([O:20][CH2:21][CH2:22][OH:23])[C:18](=[NH:17])[CH:27]=1
Reactant: Nc1ccc(OCCO)c(N)c1
Reactant: CCN(c1ccc(N)cc1)C(C)C
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CCN(c1ccc(N=C2C=C(OCCO)C(=N)C=C2N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 13.5 %

Procedure:
To a solution of 2.14 g (0.01 mol) of N-ethyl-N-isopropyl-4-aminoaniline hydrochloride and 2.41 g (0.01 mol) of 2-(2,4-diaminophenoxy)ethanol dihydrochloride in 10 ml of water and 10 ml of ethanol, brought to pH 9.5 with 20% aqueous ammonia, are added dropwise 5.7 g of 30% aqueous peroxide hydrogen solution (0.05 mol). After stirring for 6 hours at room temperature, a gum forms. The supernatant is removed and the residual gum is washed with four times of water and then taken up in dichloromethane in order to perform a chromatography (eluent: dichloromethane/methanol 98/2 v/v). 510 mg of 2-{4-amino-3-[4-(ethylisopropylamino)phenylimino]-6-iminocyclohexa-1,4-dienyloxy}ethanol hydrochloride 66 are thus obtained in the form of a black powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:12]1([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: 60 °C
Yield: 82 %

Procedure:
In a 50 mL round bottom flask was added 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by cyclohexanone (0.96 mL, 9.3 mmol). MeOH (20 mL) was added to give a clear solution followed by pyrrolidine (1 mL). A condenser was attached to the flask, and the resulting solution was heated at 60° C. overnight. MeOH was removed and the residue was redissolved in EtOAc (30 mL), washed with 1 N NaOH (10 mL) and 1 N HCl (10 mL), and then dried over Na2SO4. Solvent was removed in vacuo to give 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (2.25 g, 82%), which is used for the next step without purification.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:30](OC)=[O:31])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[C:26]([F:29])([F:28])[F:27])[CH2:16][CH2:17][CH2:18][N:11]21.O1CC[CH2:36][CH2:35]1>>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([C:30]([OH:31])([CH2:1][CH3:2])[CH2:35][CH3:36])=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Product: CCC(O)(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 7 h
Yield: 56 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 2.6 mL, 7.8 mmol) was added to a stirred solution of methyl 9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (700 mg, 1.57 mmol) in tetrahydrofuran (5.0 mL), and the mixture was stirred at 60° C. for 7 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/diisopropyl ether to give the title compound as a colorless crystal (412 mg, 0.872 mmol, 56%).
Reaction SMILES: CNC(C1C2C=C(C3C(Cl)=CN=C([NH:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]4[CH3:31])N=3)SC=2C=CC=1)=O.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49](Cl)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1.C(OC(N1CCN(CCCN)[C@@H](C)C1)=O)(C)(C)C>>[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:21][CH2:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]5[CH3:31])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1CCCN
Product: Cc1cnc(NCCCN2CCNC[C@@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, the title compound is synthesized from 2-(2-chloro-5-methyl-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and (S)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 465 [M+H].
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:5][C:4]2[N:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.O.NN.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[NH2:9][CH2:8][C:6]1[NH:7][C:2](=[O:1])[C:3]2[CH:23]=[CH:22][CH:21]=[N:20][C:4]=2[N:5]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ncccc2c(=O)[nH]1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NCc1nc2ncccc2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
A suspension of 2-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-isoindole-1,3-dione (1.0 g, 3.26 mmol) and hydrazine monohydrate (0.48 ml, 9.79 mmol) in ethanol (90 ml) was stirred at 50° C. for 3 hours. The mixture was cooled to ambient temperature and sodium carbonate (0.38 g, 3.59 mmol) and water (1 ml) were added. The suspension was stirred overnight at ambient temperature. The solid residue was filtered off, triturated with CH2Cl2/MeOH (4/1) under reflux conditions. A white solid was filtered off and triturated with TBME to yield 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (0.285 g, 1.62 mmol; 50%), as white solid. MS (m/e): 176.8 [M+H+].
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:19]C(C)([O-])C.[K+].IC.O>CS(C)=O>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[N:7]([CH3:19])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c[nH]c2ccc(C(=O)OCC)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: CCCCc1cn(C)c2ccc(C(=O)OCC)cc12
Temperature: 50 °C
Yield: 46.3 %

Procedure:
To a mixture of ethyl 3-butyl-1H-indole-5-carboxylate (0.6 g) in methylsulfoxide (10 mL) was added potassium t-butoxide (0.29 g) and iodomethane (2.0 mL). The mixture was stirred at 50° C. for 18H, at which time the mixture was pored into water (50 mL). The solution was extracted with ethyl acetate and the organic extracts washed three times with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 5% ethyl acetate in hexanes as eluent to give 0.294 g of the title compound: 1H NMR (CDCl3) δ 0.953, 1.44, 1.69, 2.77, 3.76, 4.40, 6.87, 7.26, 7.91, 8.35.
Reaction SMILES: [C:1]([O:5]C(=O)NC1CO[CH2:11][CH2:12][C@:13]([C:18]2C=C(NC(C3C=CC(C#N)=CN=3)=O)[CH:21]=[CH:20][C:19]=2F)(C(F)F)N=1)(C)(C)[CH3:2]>ClCCl.FC(F)(F)C(O)=O>[CH3:11][CH2:12][CH2:13][CH2:18][CH2:19][CH2:20][CH3:21].[CH2:1]([OH:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC
Product: CCO
Reaction time: 0.75 h
Yield: 244.9 %

Procedure:
((S)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamic acid tert-butyl ester (67.7 mg, 0.134 mmol) was dissolved in 0.75 mL dichloromethane and 0.25 mL trifluoroacetic acid. The solution was stirred at for 45 minutes and then evaporated at room temperature. The residue was dissolved in EtOAc and extracted with saturated aqueous NaHCO3 solution. The layers were washed with brine and EtOAc. The combined organic layers were dried over Na2SO4 and evaporated. The crude product was dissolved in THF, 0.2 mL HCl solution 1 mol/L in diethyl ether was added and the mixture was evaporated. The residue was crystallized from ethanol and TBME to give 48 mg of the title compound as white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=4[CH3:35])[CH2:24][CH2:23]3)[CH:21]=1)[CH2:10][C:9]2([CH3:37])[CH3:36])=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:35][C:29]1[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=1[N:25]1[CH2:24][CH2:23][N:22]([C:20]2[CH:21]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:37])([CH3:36])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=[N:18][CH:19]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(N2CCN(c3cncc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
A mixture of 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 0.60 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{5-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-pyridin-3-yl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.25 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=471.3.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>CO>[NH2:20][C:19]1[N:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[CH3:2])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccc(C)c(NN)c1
Agent: Cl
Solvent: CO
Product: Cc1ccc(C)c(-n2ncc(C#N)c2N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2,5-Dimethylphenylhydrazine hydrochloride (CAS no. 56737-78-1) (10 g, 57.92 mmol) was partitioned between EtOAc (100 mL) and NaOH (2M, aq) (60 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to afford free base of the starting material. The resultant oil was suspended in MeOH (100 mL) under nitrogen at −5° C. 2-(ethoxymethylene)malononitrile (7.07 g, 57.92 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (11.07 g, 90%) which was used without purification. 1H NMR (400 MHz, DMSO) δ 1.98 (3H, s), 2.31 (3H, s), 6.39 (2H, s), 7.07 (1H, s), 7.21-7.28 (2H, m), 7.72 (1H, s); m/z (ES+) (M+H)+=213; HPLC tR=1.79 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(N(C(C)C)CC)(C)C.Cl.Cl.[O:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1>CN(C)C=O>[Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:39][CH:36]2[CH2:35][CH2:34][N:33]([CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH2:38][CH2:37]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 70 °C
Yield: 80.8 %

Procedure:
A stirred solution of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (D53) (0.30 g, 1.04 mmole) in dimethylformamide (5 ml) at room temperature under argon was treated with diisopropylethylamine (0.59 ml, 3.3 mmole) and 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (D40) (0.28 g, 1.1 mmole) and heated at 70° C. for 1 hr. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum to leave an orange solid which was purified by chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a bright yellow solid (0.38 g, 81%). MH+=452, 454.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH:15]=[C:14]([Cl:13])[CH:18]=[N:17]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Clc1cn[nH]c1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2cc(Cl)cn2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, 4-chloropyrazole and cesium carbonate in NMP. EI-MS m/e (%): 269 (M{37Cl}+H+, 30). 267 (M{35Cl}+H+, 100).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][C:19]#[C:20][C:21]([OH:23])=O.[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:42])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1>O1CCCC1.N1C=CC=CC=1>[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:42][C:21](=[O:23])[C:20]#[C:19][CH2:18][O:17][CH3:16])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: COCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: COCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Isobutyl chloroformate (0.432 g, 3.2 mmol) and N-methylmorpholine (0.959 g, 9.48 mmol) were added to an ice cold solution of 0.720 g (6.32 mmol) of 4-methoxy-but-2-ynoic acid in 30 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 0.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 8 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.270 g of 4-Methoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 411.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:23]([NH2:26])[CH2:24][NH2:25]>C1C=CC=CC=1>[NH2:25][CH2:24][CH2:23][N:26]1[CH2:2][C:3]2[C:4](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1C(O)c1ccccc1
Reactant: NCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: NCCN1Cc2ccccc2C1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol was dissolved in 900 ml. of benzene, 80 g. of anhydrous magnesium sulfate was added and the mixture was cooled in an ice bath. Hydrogen bromide was bubbled into the stirred solution until saturation which took about 30 minutes. During this time the temperature of the solution was kept at 15°-18°. The ice bath was removed and the temperature was allowed to rise to 35° in the course of 1 hour. The mixture was heated for another hour at 40°-45° on a steam bath. During the whole time hydrogen bromide was passed into the solution to keep it saturated. The mixture was filtered and the solution was concentrated in vacuo to give a red oil which was dissolved in 200 ml. of benzene and added to 342 g. (5.7 moles) of ethylenediamine in the course of 15 minutes. During the addition the mixture was stirred and cooled to maintain a temperature of ca. 40° . The mixture was stirred at 25° for 70 minutes. Two layers were obtained and separated. The benzene layer was washed with water and concentrated in vacuo. The residual oil was dissolved in 250 ml. of ether. This solution was extracted twice with 300 ml. of cold 1N hydrochloric acid. The acidic aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with 350 ml. of ether. The ethereal solution was washed with 250 ml. of water, dried and concentrated. The residue was an amber oil which crystallized on scratching. This material melted up to ca. 45°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate (48.53 g, 236 mmol) in anhydrous dichloromethane (1 L) was cooled to 0° C. Triethylamine (49.4 mL, 354 mmol)) was added. Methanesulfonyl chloride (20.10 mL, 260 mmol) was added dropwise over a period of 10 minutes. The reaction was allowed to warm to ambient temperature and stir overnight. The reaction was quenched with saturated sodium bicarbonate solution (500 mL). The organic layer was washed with water (3×500 mL) and brine (1×500 mL), dried over sodium sulfate and then concentrated under reduced pressure to provide 66.9 g of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1.[CH3:18][NH2:19].O>O1CCCC1.C(N(CC)C(C)C)(C)C>[I:8][C:7]1[C:2]([NH:19][CH3:18])=[N:3][C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: N#Cc1ccc(Nc2ncc(I)c(Cl)n2)cc1
Reactant: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(C#N)cc2)ncc1I
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 4-((4-chloro-5-iodopyrimidin-2-yl)amino)benzonitrile (J12, 25 mg) in tetrahydrofuran (1 mL), N,N-diisopropylethylamine (37 μL) and a 2.0 mol/L solution of methylamine in tetrahydrofuran (105 μL) were added at room temperature, and the mixture was stirred at room temperature for 19 hours. To the reaction mixture, water (5 mL) was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 4-((5-iodo-4-(methylamino)pyrimidin-2-yl)amino)benzonitrile (F224, 27 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1>>[C@H:16]1([NH:15][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:31]([C:29]3[N:28]=[CH:27][N:26]([CH3:25])[CH:30]=3)(=[O:33])=[O:32])[N:9]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cn1cnc(S(=O)(=O)Nc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)c1

Procedure:
The title compound, MS: m/e=420.3 (M+H+), was prepared in accordance with the general method of example 45 from 5-nitro-2-chloroquinoline, (R)-1-aminoindane and 1-methylimidazol-4-sulfonylchloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH2:15][CH3:16])=[O:7]
Reactant: CN(C)CCCN=C=N
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
4-Methylsalicylic acid (304 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 4-methylsalicylate (175 mg, yield 49%).