Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([O:26]CC)=[O:25])[C:15]=3[CH3:29])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=3[CH3:29])=[CH:11][CH:10]=2)=[O:7])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(4-chlorobenzamido)benzyl]-2-methyl-1H-indol-1-yl]acetate (580 mg, 1.26 mmol), lithium hydroxide monohydrate (159 mg, 3.79 mmol), 10 mL tetrahydrofuran, 10 mL methanol, 10 mL water were weighed, and stirred at room temperature for 1 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. It was filtered, and the filter cake was washed with 20 mL methanol to obtain the product as a white solid 523 mg, at a yield of 95.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:17][CH3:18])([CH3:16])[CH2:14][CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:17][CH3:18])([CH3:16])[CH2:14][CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(C)(CC)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(C)(CC)N=C=Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 4.5 g of N-(3,5-dichlorophenyl)-N'-(1-ethyl-1-methylpropyl)thiourea produced in Example A-5 and 5.8 g of triphenylphosphine in 60 ml of dichloromethane were added 2.2 g of triethylamine and 3.4 g of carbon tetrachloride. The mixture was refluxed for 4 hours, cooled to room temperature and evaporated in vacuo. The residue was stirred with n-hexane and the resulting solid matter was removed by filtration. The filtrate was evaporated to give N-(3,5-dichlorophenyl)-N'-(1-ethyl-1-methylpropyl)carbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 3.4 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 40 minutes, cooled to room temperature and poured into water. The resulting crystals were filtered off and recrystallized from benzene to give 3.5 g of the title compound as colorless flakes melting at 148.0°-150.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:24])=[C:21]([C:22]#[N:23])[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CS(C)=[O:27].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:24])=[C:21]([C:22]([NH2:23])=[O:27])[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C#N)c(C)sc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C(N)=O)c(C)sc2n1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 3-chloro-N-(3-cyano-2,6-dimethylthieno[2,3-b]pyridin-4-yl)benzenesulfonamide (Example 73) (119 mg, 0.315 mmol), DMSO (3 mL) and aqueous NaOH (3M) (1.05 mL, 3.15 mmol) was stirred at 150° C. for 5 h. The mixture was then cooled and acidified with 5M HCl to pH 3-4. Water (20 mL) was added and the mixture extracted with ethyl acetate (3×10 mL). The organic layer was then dried over MgSO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-10% MeOH in DCM, and then further triturated with MeOH, to give the title compound (69 mg). LCMS (A) m/z: 396 [M+1]+, Rt 1.13 min (acidic).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN1C(=O)CCC1.O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
A suspension of 3-fluoronitrobenzene (23 ml; 0.21 mol) and piperazine (55.5 g; 0.64 mol) in anhydrous NMP (30 ml) was heated to 70° C. for five days. The cooled mixture was diluted with water (250 ml) and extracted with dichloromethane. The combined extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel eluting subsequently with mixtures of ethyl acetate and methanol (4:1 v/v) and (1:1 v/v) to leave the desired product as oily crystals (30.7 g; 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN1CCCC1=O>[ClH:8].[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:1][C:2]2[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Cc1nc(C)c(Cl)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)cc2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.5 %

Procedure:
A solution of 73.4 g (0.465 mol) of 4-amino-5-chloro-2,6-dimethylpyrimidine in 370 ml of anhydrous N-methylpyrrolidone is added dropwise over 45 min under a nitrogen atmosphere at room temperature to a suspension of 19.5 g (0.49 mol) of sodium hydride (60% suspension in liquid paraffin) in 80 ml of anhydrous N-methylpyrrolidone. The mixture is stirred at room temperature for 1 h and then cooled to 4° C. Then a solution of 111.0 g (0.465 mol) of 4-benzyloxybenzyl chloride in anhydrous N-methylpyrrolidone is added dropwise, with vigorous stirring, at a rate such that the internal temperature does not rise higher than 5° C. (about 1 h). Thereafter, the mixture is warmed to room temperature and stirred for 1 h. The solution is subsequently poured into 4 l of water and extracted with ethyl acetate (3×1 l). The combined organic extracts are washed with water (2 l), dried over sodium sulfate and concentrated. The oil (180 g) which remains is dissolved in 400 ml of isopropanol and is admixed dropwise with stirring with 100 ml of saturated ethereal hydrochloric acid. Thereafter, further ethyl acetate is added and the mixture is stirred at room temperature for 1 h for complete precipitation of the hydrochloride. The precipitate is filtered off with suction, washed with ethyl acetate (500 ml) and dried in a vacuum drying cabinet at 40° C. 114.8 g (63%) of the title compound are isolated as a beige solid. m.p.: 227° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:15]3[C:11]([O:12][CH:13]=[CH:14]3)=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.C(O)CC.O.[NH2:29][NH2:30]>C(Cl)Cl>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:9]1[N:10]=[C:11]2[N:15]([C:8]=1[C:5]1[N:6]=[N:7][C:2]([NH:29][NH2:30])=[CH:3][CH:4]=1)[CH:14]=[CH:13][O:12]2
Reactant: NN
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccc(Cl)nn2)c(F)c1
Solvent: O
Solvent: CCCO
Solvent: ClCCl
Product: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)nn1
Temperature: 100 °C
Yield: 77.2 %

Procedure:
To a flask was added 5-(6-chloropyridazin-3-yl)-6-(2,4-difluorophenyl)imidazo[2,1-b]oxazole (4.00 g, 12.0 mmol), 1-propanol (80 mL) and hydrazine hydrate (5.89 mL, 120 mmol). The reaction mixture was heated at about 100° C. for about 20 h. The reaction mixture was cooled to ambient temperature and then diluted with DCM (100 mL). The organic layer was washed with saturated aqueous NaHCO3 (80 mL), dried with MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.04 g, 77%) as a solid. LC/MS (Table 1, Method g) Rt=1.58 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]2[C@H:26]3[C@@H:22]([N:23]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=4)[C:24](=[O:27])[O:25]3)[CH2:21][S:20](=[O:40])(=[O:39])[CH2:19]2)=[CH:13][C:12]=1[F:41])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]2[C@H:26]3[C@@H:22]([N:23]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([CH3:37])([CH3:38])[CH3:36])[CH:30]=4)[C:24](=[O:27])[O:25]3)[CH2:21][S:20](=[O:39])(=[O:40])[CH2:19]2)=[CH:13][C:12]=1[F:41]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(NC(=O)OCc5ccccc5)c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(N)c(F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
A solution of {4-[(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-phenyl}-carbamic acid benzyl ester (9.6 g, 15.8 mmol) in THF-MeOH 1:2 (150 mL) was hydrogenated over 10% Pd/C (0.7 g) for 4 h at 45° C. and 1 bar. The catalyst was filtered off over Celite and the filtrate is evaporated to provide the title compound as a colorless solid: TLC (toluene-EtOAc 3:1) Rf=0.26; UPLC RtD=1.596 min; ESIMS [M+NH4]+=478; 1H NMR (600 MHz, DMSO-d6): δ 7.38 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.13 (d, 1H), 6.83 (d, 1H), 6.69 (m, 2H), 5.02 (s, 2H), 4.42 (d, 1H), 4.22 (d, 1H), 4.11 (t, 1H), 3.67 (m, 2H), 3.46 (t, 1H), 3.01 (m, 2H), 2.79 (dd, 1H), 2.44 (m, 2H), 1.26 (s, 9H).
Reaction SMILES: [C:1]([C@H:3]1[C@H:8]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C:5](=[O:25])[CH2:4]1)[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[CH2:15][C@:16]1(O)[CH3:22])[CH2:11][CH2:10]3)#[N:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([C@H:3]1[C@H:8]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C:5](=[O:25])[CH2:4]1)[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[CH:15]=[C:16]1[CH3:22])[CH2:11][CH2:10]3)#[N:2]
Reactant: C[C@]12[C@@H](CC[C@H]3[C@@H]4[C@H](C#N)CC(=O)[C@@]4(C)CC[C@@H]31)CC(=O)C[C@@]2(C)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1=CC(=O)C[C@@H]2CC[C@H]3[C@@H]4[C@H](C#N)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]12C
Temperature: 0 °C
Yield: 89.7 %

Procedure:
2.0 g of 15β-cyano-1β-hydroxy-1α-methyl-5α-androstane-3,17-dione is stirred in 20 ml of glacial acetic acid with 6 ml of trifluoroacetic anhydride at room temperature. After 4 hours the solution is added to ice/water. The precipitated product is suctioned off, dissolved in ethyl acetate and washed with water. 1.7 g of 15β-cyano-1-methyl-5α-androst-1-ene-3,17-dione with a melting point of 193° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[CH3:10][CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(O)(=O)C>[C:12]1([CH:11]([N:18]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(N=C(O)/C(Cl)=C(/Cl)C(=O)O)c1ccccc1
Yield: 72.2 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 12.0 g (0.1 mol) of α-methylbenzylamine are heated in 100 ml of glacial acetic acid at the boiling point for 4 hours. 100 ml of water are then added and the oil which has separated out is extracted with methylene chloride. The methylene chloride phase is separated off, washed with water, dried and evaporated. The oil which remains cystallizes. 20.8 g (77.3% of theory) of dichloromaleic acid N-1-phenylethylimide of melting point 62°-65° C. are obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[N+:32]([O-])([OH:34])=[O:33]>>[CH2:9]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[N+:32]([O-:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCN(C)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCCCN(C)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
Add 23.6 g (0.22 mol) N-methylaniline into 92 g (0.2 mol) 14% hexane solution of N-butyllithium and stir it for 10-20 minutes. Drop 33.3 g (0.1 mol) octadecylbromide into the above solution, while stirring it. Add 200 ml water into the solution, after heating and refluxing the solution for about 17 hours and cooling it down to room temperature. Add 6N hydrochloric acid to the solution after concentrating the solution extracted by 300 ml diethyl ether and deposit it. 32.3 g (0.09 mol) N, N-methyloctadecylaniline is obtained by refinement through crystalization with ethyl alcohol and water. Dissolve the obtained 32.3 g (0.09 mol) N, N-methyloctadecylaniline into 250 ml concentrated sulfuric acid. Add 30 ml concentrated nitric acid into the solution while stirring it in an ice water bath. Leave it about one hour after adding the nitric acid. Add the solution into ice water filter off the deposit from it, and refine it by crystalization with ethyl alcohol and water. With the above step, 14.5 g (0.036 mol) N, N-octadecylmethyl-o-nitroaniline is obtained. Add 100 ml 2N hydrochloric acid into this 14.5 g (0.036 mol) N, N-octadecylmethyl-o-nitroaniline which is dissolved into 200 ml ethyl alcohol. 11.7 g (0.031 mol) N, N-octadecylmethyl-o-phenylene-diamine is obtained after adding 11.75 (0.18 mol) zinc dust into the above solution to be heated and refluxed for one hour.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:22][C:23](O)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[O:31]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1.P(C#N)(=O)(OCC)OCC>O.C(N(CC)CC)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([CH2:22][C:23]([N:38]4[CH2:39][CH2:40][C:35]5([O:34][CH2:33][CH2:32][O:31]5)[CH2:36][CH2:37]4)=[O:24])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C1CC2(CCN1)OCCO2
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCC2(CC1)OCCO2
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
To a mixture of 20.4 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetic acid and 250 ml of dimethylformamide were added 16 ml of triethylamine, 10.4 g of 1,4-dioxa-8-azaspiro[4.5]decane and 16 ml of diethyl phosphorocyanidate, and the mixture was stirred for 20 minutes. After addition of water, the resulting crystalline precipitate was collected by filtration, washed with water and dried to give 26.4 g of crude crystals. Recrystallization from methylene chloride-ethyl acetate gave 27.1 g of colorless crystals melting at 238°-239° C.
Reaction SMILES: C(C1C=CC(NCC([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)O)=CC=1)(OCC)=O.P([O-])([O-])O.[Na+].[Na+].C=O.[O:38]1[CH2:43][CH2:42]OCC1>>[CH3:27][C:22]1([CH3:26])[CH2:21][CH2:20][C:19]([CH3:28])([CH3:29])[C:18]2[CH:17]=[C:16]([CH:42]3[CH2:43][O:38]3)[CH:25]=[CH:24][C:23]1=2
Reactant: C1COCCO1
Reactant: CCOC(=O)c1ccc(NCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: C=O
Agent: [Na+]
Agent: [O-]P([O-])O
Product: CC1(C)CCC(C)(C)c2cc(C3CO3)ccc21

Procedure:
1.58 g (4 millimoles) of N-(4-carbethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-aminoethanol were stirred with 20 ml of 1N sodium hydrogen phosphite solution and 2 ml (20 millimoles) of formalin solution in 20 ml of dioxane for 1 hour at 60° C. The mixture was then poured onto water and extracted with ether, and the organic phase was washed with 2N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated down. Recrystallization from methanol gave 1.0 g of the title compound, RF =0.51 (thin layer chromatography, silica gel; 7:1 n-heptaneethyl acetate).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:45][N:46](C(C)C)C(C)C.CN>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][NH:46][CH3:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 40 °C
Reaction time: 12 h
Yield: 12.7 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.2 mL) and DIPEA (17 μl, 0.10 mmol) was added methylamine (2.0M solution in THF) (41 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were contaminated with an impurity; the crude material was re-purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylamino) acetamide (Example 13) as a light brown solid (6 mg, 12%): m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.32 (3H, s), 2.39 (3H, s), 3.28 (2H, s), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.63-7.55 (3H, m), 7.93 (1H, m), 8.37-8.30 (3H, m), 8.59 (1H, s), 8.80 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (900 mg, 2.8 mmol) in CH2Cl2 (100 mL) at 0° C., ethanesulfonyl chloride (0.8 mg, 8.4 mmol) and triethylamine (1.6 mL, 11.2 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min., after which time the mixture was partitioned between CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (50 mL×2) and the combined organic phase dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by solid phase extraction on a 500 mg aminopropyl column (International Sorbent Technologies) eluting with chloroform (30 mL×2) and ethyl acetate (50 mL) to give 800 mg of the title compound (69%).
Reaction SMILES: O=[C:2]([CH2:7][CH3:8])[C:3](OC)=[O:4].[F:9][C:10]1[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=1[CH2:12][N:13]1[C:17]2=[N:18][CH:19]=N[CH:21]=[C:16]2[C:15]([C:22](=[NH:25])[NH:23][NH2:24])=[N:14]1.[CH2:30](O)C>>[CH2:7]([C:2]1[N:24]=[N:23][C:22]([C:15]2[C:16]3[C:17](=[N:18][CH:19]=[CH:30][CH:21]=3)[N:13]([CH2:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[F:9])[N:14]=2)=[N:25][C:3]=1[OH:4])[CH3:8]
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Reactant: CCC(=O)C(=O)OC
Reactant: CCO
Product: CCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O

Procedure:
0.817 g (7.035 mmol) of methyl 2-oxobutanoate in 15 ml of ethanol were initially introduced and heated to reflux. Then, 2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 20 ml of ethanol were added and the mixture was heated under reflux overnight. After cooling, the mixture was filtered off with suction, and the filtercake was washed with a little ethanol and dried under high vacuum. This gave 1.83 g of the target compound (74% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O.CCOC(C)=O.O.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>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: Nc1ncc(Br)cn1
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1ncc(-c2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-pyrimidin-2-ylamine (0.8 g, 4.59 mmol), 4-bromophenyl boronic acid (1 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.259 mmol), cesium carbonate (1.15 g, 3.03 mmol) was stirred in MeOH/H2O (20 ml, 1/1) at reflux temperature overnight. The reaction was cooled to room temperature and diluted with EtOAc (200 ml) and water (50 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding a residue which was purified on silica gel eluting with 85% v/vEtOAc/hexanes yielding product 81 as white solid. (0.7 g, 63%). ESMS (MH, 250).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CCO[C:44]([CH3:46])=O.[CH3:47][C:48]#N.O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C:27]1[CH:32]=[CH:31][C:30]([C:9]2[CH:10]=[CH:11][C:48]([CH2:47][CH2:44][CH3:46])=[CH:13][CH:8]=2)=[CH:29][CH:28]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#N
Reactant: CCOC(C)=O
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCc1ccc(-c2ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)[C@@H]3C[C@H]3c3cccc(F)n3)cc2)cc1
Temperature: 140 °C

Procedure:
A mixture of [(1S,2S)-1-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid t-butyl ester (78 mg, 0.146 mmol), arylboronic acid (0.18 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2CO3 (38 mg, 0.27 mmol) in CH3CN/H2O (3.5/0.5 mL) was heated in a macrowave at 140° C. for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 574).