Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:22][CH2:21][CH2:20][CH2:19]2
Reactant: CC=CCC1C(=O)c2cc(C)ccc2C12CCCC2
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Reaction time: 1 h
Yield: 99 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 12.7 g of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one in 250 ml of anhydrous dichloromethane and 50 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.54 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 160 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 2.5 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloro-methane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 12.0 g (99%) of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one were obtained as a light red oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1Br)[CH3:2].[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[B:17]([OH:20])[OH:18])[CH3:2]
Reactant: COB(OC)OC
Reactant: CCc1cccc(CC)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
2,6-Diethyl bromobenzene (38.2 g, 180.2 mmol) is added dropwise through an additional funnel over a 1 hour period to a solution of n-BuLi (2.0 M in cyclohexane, 99.1 mL, 198.2 mmol) in THF (380 mL) at −75° C. After addition, the reaction mixture is stirred at −75° C. for 30 minutes; trimethyl borate (28.1 g, 270.3 mmol) is added slowly over a 40 minute period. The reaction mixture is warmed to room temperature overnight. 2N HCl (250 mL) is added slowly and the resulting mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ether (2×200 mL). The combined organic layers are dried over anhydrous Na2SO4 and the solvents are removed in vacuo. Hexane (400 mL) is added to the residue and a white precipitate is formed. Filtration and drying in vacuo give 2,6-diethylphenyl boronic acid as a white solid. 1H NMR: (CDCl3) 7.22 (t, 1H), 7.04 (s, 2H), 4.65 (s, 2H), 2.64 (q, 4H), 1.22 (t, 6H).
Reaction SMILES: C([Li])CCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[O:32].[Cl-].[NH4+]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:25]1([OH:32])[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)[NH:27][C:26]1=[O:31]
Reactant: c1ccc2scnc2c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (35 ml, 56 mmol) was added dropwise to a solution of benzothiazole (6.2 ml, 56 mmol) in THF (100 ml) at −78° C. After stirring at −78° C. for 1.5 h, the solution of the lithiated benzothiazole was transferred via a needle into an ice-cold suspension of 5-chloroisatin (3.63 g, 20 mmol) in THF (70 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure, during which the intermediate starts to crystallize. Filtration and drying yielded 4.47 g of the intermediate as yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCCC1=O>CO>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Solvent: CO
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-chloroaniline (365 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→15:75) and recrystallized from ethanol-ethyl acetate to give the title compound (226 mg) as a pale-brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:13]([O:17][C:18]([N:20]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:20]([CH3:21])[C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:31][CH:30]=2)=[O:28])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN(Cc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Reactant: NNC(=O)c1nc(Br)cnc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(C(=O)NNC(=O)c2nc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbohydrazide (12.91 g, 55.64 mmol), 4-[[tert-butoxycarbonyl(methyl)amino]methyl]benzoic acid (14.76 g, 55.64 mmol) and triethylamine (12.39 g, 17.07 mL, 122.4 mmol) were suspended in N,N-dimethylformamide (200 mL) and stirred at ambient temperature for 30 minutes. A further 3-amino-6-bromo-pyrazine-2-carbohydrazide (3 g, 12.93 mmol) was added and left to stir for 18 hours at ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the N,N-dimethylformamide. The residue was then diluted with ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution followed by a brine wash. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to a yellow sticky solid. The solid was triturated with ethyl acetate to give a beige solid (this is the hydrazide starting material), the crude mother liquors were concentrated and purified by column chromatography (ISCO Companion XL, 330 g gold column) dry loaded and eluted with 30 to 70% ethyl acetate/petroleum ether to give a yellow sticky gum. This gum was then crystallised from petroleum ether to give tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carbonyl)hydrazinecarbonyl)benzyl(methyl)carbamate as a yellow powder (14.16 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.20 (m, 1H), 1.38-1.45 (br d, 9H), 2.80 (br s, 3H), 4.02-4.04 (m, 1H), 4.45 (s, 2H), 7.34 (d, 2H), 7.69 (br s, 2H), 7.89 (d, 2H), 8.44 (s, 1H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O>>[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:2]1[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 2-methoxyphenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](C2C=CC=C(S(C3C=C4C(=C(C)C=3)N=CC(C(N)=O)=C4NC3C=CC=C(OC)C=3)(=O)=O)C=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([S:48]([C:51]2[CH:52]=[C:53]3[C:58](=[C:59]([CH3:61])[CH:60]=2)[N:57]=[CH:56][C:55]([C:62]([NH2:64])=[O:63])=[C:54]3[NH:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([O:72][CH3:73])[CH:67]=2)(=[O:50])=[O:49])=[CH:44][CH:43]=1>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([C:51]3[CH:52]=[C:53]4[C:58](=[C:59]([CH3:61])[CH:60]=3)[N:57]=[CH:56][C:55]([C:62]([NH2:64])=[O:63])=[C:54]4[NH:65][C:66]3[CH:71]=[CH:70][CH:69]=[C:68]([O:72][CH3:73])[CH:67]=3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(Br)cc4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CO)cc5)cc4)cc23)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 64, using Intermediate 63 (1.38 mmol) as substrate. The crude product was triturated in 15 mL of ethyl acetate for 10 min. After cooling to room temperature, the suspension was recovered by filtration and washed with ethyl acetate to give the title compound as a yellowish solid (591 mg, 77% for 3 steps). ES/MS calcd. for C31H28N3O5S+ 554.2. Found m/z=554.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:33]1[O:34][C:35]([CH3:38])=[N:36][N:37]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][N:26]([C:33]5[O:34][C:35]([CH3:38])=[N:36][N:37]=5)[CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1nnc(Br)o1
Reactant: FC1CNCCC1Nc1nc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccn2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnc(N2CCC(Nc3nc4c(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cccn4n3)C(F)C2)o1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 269b, 68 mg, 152 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) and diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) dissolved in dry dioxane (2 mL) was stirred at 70° C. for 12 hours and then at 110° C. for 1 hour. Further diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) were added and heated to 110° C. for another hour. The solvent was evaporated and the residue directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as colorless oil (46 mg, 57%) as a mixture of cis- and trans-isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH2:30])[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH:30][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C1CCc2cc(F)ccc2C1
Reactant: CCC[C@H](N)C(=O)Nc1cc(CC2CCCC2)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC1CCc2cc(F)ccc2C1)C(=O)Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Fluoro-3,4-dihydro-1H-naphthalen-2-one (0.2 mmol) was combined with 2-(S)-Amino-pentanoic acid (5-Cyclopentylmethyl-isoxazol-3-yl)-amide (0.2 mmol) in 2 mL of anhydrous dichloromethane under N2. Sodium triacetoxyborohydride (0.3 mmol) and two drops acetic acid were added and the reaction was stirred at rt for 16 h. The crude solution was then concentrated under reduced pressure and purified through flash chromatography on silica gel to give 2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-cyclopentylmethyl-isoxazol-3-yl)-amide, LC-MS: retention time 2.0 min, M+1: 414.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:30](=[O:31])[N:29]([CH3:32])[C:13]2[N:14]([CH3:28])[C:15]3[C:20]([C:12]=2[CH:11]=1)=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23][N:24](C)C)=[CH:17][CH:16]=3.O.[NH2:34]N>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:30](=[O:31])[N:29]([CH3:32])[C:13]2[N:14]([CH3:28])[C:15]3[C:20]([C:12]=2[CH:11]=1)=[CH:19][C:18]([C:21]1[NH:34][N:24]=[CH:23][CH:22]=1)=[CH:17][CH:16]=3
Reactant: NN
Reactant: COc1ccc(-c2cc3c4cc(C(=O)C=CN(C)C)ccc4n(C)c3n(C)c2=O)c(Cl)c1
Solvent: O
Product: COc1ccc(-c2cc3c4cc(-c5ccn[nH]5)ccc4n(C)c3n(C)c2=O)c(Cl)c1

Procedure:
The process is carried out as indicated in Example 60 above, using compound D 3-(2-chloro-4-methoxyphenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.
Reaction SMILES: C(NC(C)C)(C)C.[O:8]=[C:9]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][NH:10]1.Br[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([S:38]([C:41]2[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH:30]=1>C1COCC1>[O:8]=[C:9]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH2:13][CH2:12][CH2:11][N:10]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=2)(=[O:40])=[O:39])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CBr)c3ccccc32)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.238 mL, 8.60 mmol) in THF (40 mL) n-butyllithium (6.01 mL, 9.61 mmol) was added at 0° C. and the mixture was stirred for 30 min at 0° C. Then a solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (2.57 g, 9.28 mmol) in THF (10 mL) was added within 3 min and the mixture was stirred for 30 min at 0° C. 3-(bromomethyl)-1-tosyl-1H-indole [58550-81-5] (3.2 g, 8.43 mmol) in THF (10 mL) was dropped to the reaction mixture within 15 min. The mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with TBME (2×150 mL). The combined organic layers were washed with 5% aqueous citric acid and brine, dried over anhydrous Na2SO4, filtered and concentrated (5.3 g, 100%). [1H NMR (400 MHz, DMSO-d8) ♀ ppm 7.88 (d, J=8.28 Hz, 1H), 7.81 (d, J=8.28 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.36 (d, J=8.03 Hz, 2H), 7.32 (t, J=7.91 Hz, 1H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.75-3.63 (m, 2H), 3.09 (t, J=5.77 Hz, 2H), 2.99 (br. s., 2H), 2.30 (s, 3H), 1.90-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.39 (s, 9H), 1.36-1.28 (m, 2H); LCMS RtA=1.37 min, [M+H]+=552.3].
Reaction SMILES: [NH2:1][C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[O:26][CH3:27])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:16].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([C:2]2([NH:1][C:35](=[O:37])[CH3:36])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[NH:12][C:13](=[O:15])[CH3:14])[C:3]2=[O:16])=[C:18]([O:26][CH3:27])[CH:19]=1)([CH3:25])[CH3:24]
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2cccc(NC(C)=O)c2C1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2cccc(NC(C)=O)c2C1=O
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of N-(2-amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-indene-4-yl)acetamide (0.20 g, 0.54 mmol) in dichloromethane (10 mL) and was added triethylamine (0.23 mL, 1.6 mmol) and acetyl chloride (0.040 mL, 0.56 mmol) and then stirred for overnight. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (50% ethylacetate in hexane) to afford the title compound (210 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C1C(=O)N([Cl:29])C(=O)C1>>[Cl:29][C:10]1[C:11]2[C:6](=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:3][C:2]=2[F:1])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1F
Product: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.30 g, 1.05 mmol) and NCS (0.17 g, 1.26 mmol) according to method C to yield 0.21 g (62%) of a light orange solid: mp 126-128° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.25-7.31 (1H, m), 7.35 (1H, d, J=8.91 Hz), 7.64-7.67 (1H, m), 7.70-7.78 (2H, m), 7.87 (1H, dd, J=1.58 Hz, J=9.04 Hz), 10.68 (1H, s); MS (ESI) m/z3191321 (M−H)−.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH2:25][C:26]([CH3:34])([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH3:27])[N:20]=[C:19]([Cl:35])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:35][C:19]1[NH:20][C:21]([NH:24][CH2:25][C:26]([CH3:34])([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH3:27])=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCC(C)(C)N2CCOCC2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(CNc1[nH]c(Cl)nc(=NN)c1F)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a suspension of tris(1,1-dimethylethyl)2-(2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.578 g, 0.94 mmol) in MeOH (8 mL) was added 4M HCl in 1,4-dioxane (8 mL), and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the crude residue was treated with an aqueous K2CO3 extractive workup to provide 2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4(1H)-pyrimidinone hydrazone as a brown oil (0.249 g). LCMS: (M+H)+=319.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-])=O)[C:9]#N)=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][C:12]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[NH:19][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CC(C#N)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2
Temperature: 40 °C
Reaction time: 24 h
Yield: 31.6 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(5-methyl-2-nitrophenyl)propanenitrile (0.3 g, 0.00105 mol), and 10% Pd on Carbon (0.180 g) in THF (1 mL) and MeOH (6 mL) was stirred under atmospheric hydrogen pressure at 40° C. for 24 h. After completion of reaction (monitored by TLC), the catalyst was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and the product was purified by column chromatography (4% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to give the desired compound as a yellow colored solid (0.080 g, 33% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([C:8]#N)[CH:7]=1.C(O)=[O:12]>O.C1(C)C=CC=CC=1.[Ni].[Al]>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[C:6]([CH:8]=[O:12])[CH:7]=1
Reactant: N#Cc1cnc(Cl)c(Br)c1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cnc(Cl)c(Br)c1
Reaction time: 48 h

Procedure:
3-Bromo-2-chloro-5-cyanopyridine (8.6 g) in 90% formic acid (40 ml) and water (10 ml) were treated with Raney nickel/aluminum alloy (8.0 g) and the mixture stirred and heated to 55°-60° for 6 hours. The mixture was left to stand for two days, and then filtered. The filtrate was diluted to 500 ml with water and extracted with ether (2×250 ml). The ether extract was washed with aqueous sodium carbonate, dried, and evaporated to give an oil. The oil was diluted with toluene which was then removed under reduced pressure. The residue was diluted with a little ether, the solution filtered, and the filtrate evaporated to give an oil identified as the required aldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]([C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[CH:28]=1)=[O:23]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:33][C:30]3[CH:31]=[CH:32][C:26]4[O:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:28][C:27]=4[CH:29]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: CC(C)(C)c1cccc(Nc2nc(Cl)ncc2F)c1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)(C)C)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine, N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to give N4-(3-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine. LCMS: retn, time: 26.76 min.; purity: 97%; MS (m/e): 435 (MH+); 1H NMR (DMSO-d6): δ 9.41 (2H, sl), 8.27 (1H, s), 8.21 (1H, d, J=3.9 Hz), 7.98 (1H, m), 7.77-7.60 (3H, m), 7.37 (1H, t, J=8.1 Hz), 7.22 (1H, d, J=8.1 Hz), 3.98 (3H, s), 1.34 (9H, s).