Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:11](=O)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]1([CH2:7][N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)/[C:11](=[N:30]/[NH:29][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=O)c1ccccc1
Reactant: COc1ccc2c(c1)N(CC1CCCCC1)C(=O)C2=O
Product: COc1ccc2c(c1)N(CC1CCCCC1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1-cyclohexylmethyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3-d6): δ 1.01-1.09 (m, 2H), 1.16 to 1.26 (m, 3H), 1.68-1.86 (m, 6H), 3.56 (d, 2H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.58 (t, 1H), 7.80 (d, 1H), 8.01 (d, 2H), 13.98 (br s, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:23]=[CH:22][S:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35](Cl)=[O:36]>C(Cl)Cl>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([N:16]1[CH2:17][CH:18]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)=[O:36]
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(F)c1)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccsc2)C1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 0.023 g (0.071 mmol) of 3-(SR)-(4-phenylpiperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine and 0.079 mL of Et3N in 2 mL of CH2Cl2 was added 0.059 g (0.28 mmol) of 3,4-difluorobenzoyl chloride and the reaction mixture was stilled for 0.5 h. The reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3 solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone: hexanes, 1:3) to give 0.026 g of the title compound. 1H NMR (CDCl3) δ7.17-7.49 (m, 9H), 7.13 and 7.08 (s, 1H), 7.04 and 6.99 (d, 1H, J=4.6 Hz),4.08-4.15 (m, 2H); Mass Spectrum (CI) m/e=482 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]([CH2:21][C:22](=[O:24])[CH3:23])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-bromophenoxy)-1H-benzo[d]imidazole (5.72 g) in DMF (60 mL) was added NaH (60% in oil, 950 mg) at 0° C. After stirring for 5 min, chloroacetone (2.36 mL) was added to the mixture at 0° C. The mixture was stirred at room temperature for 5 h. The mixture was diluted with AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt in hexane) and recrystallized from THF/Et2O to give the title compound (3.47 g).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([OH:40])=[O:39])([C:34]([OH:36])=[O:35])[OH:33].CO>O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([O-:40])=[O:39])([C:34]([O-:36])=[O:35])[OH:33]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: O
Solvent: CO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 22.5 °C

Procedure:
In another example sunitinib base and molar equivalent of citric acid are dissolved, while heating, in the mixture of methanol and water, preferably in 1:1 volumetric ratio. The solution is subsequently left to cool to about room temperature such as about 20 to 25° C. to give sunitinib citrate.
Reaction SMILES: [NH:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)N.[H][H]>CO.C1COCC1.[Ni]>[NH2:1][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:21])[CH3:22])[CH:14]=2)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)Oc1cccc(-n2c(NN)nc3ccccc3c2=O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(-n2c(N)nc3ccccc3c2=O)c1
Reaction time: 40 h

Procedure:
A solution of 2-Hydrazino-3-(3-isopropoxy-phenyl)-3H-quinazolin-4-one (2.5g, 8.0 mmol) in 100 mL methanol-THF (1:1) was treated with Raney Ni (2.0), and resulting suspension was subjected to atmosphere of hydrogen at 52.0 psi for 30 hours with agitation at temperature of 50° C. An additional 1.0 g of Raney Ni was added and reaction was continued for additional 40 hours at 50° C. The mixture was then filtered through celite, and the solvent was removed in vacuo to give the title compound as a reddish yellow solid. This crude product was then titurated with ethyl acetate and hexane to isolate 1.85 g (78%) product as a light yellow solid, mp 130°-133° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(NCC)C.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCNCC
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 50.2 %

Procedure:
In 50 ml of diethylamine were dissolved 5.0 g (22 mmol) of 4-bromo-α, α,α-trifluorotoluene and 1.25 g (22 mmol) of propargyl alcohol, and 80 mg (0.11 mmol) of bis(triphenylphosphine)palladium (II) chloride and 40 mg (0.22 mmol) of copper (I) iodide were added to the solution, followed by stirring of the resulting mixture at 50° C. for 35 minutes. To the mixture were added 40 mg (0.06 mmol) of bis(triphenylphosphine)palladium (II) chloride, and the resulting mixture was stirred for a further 35 minutes. After the mixture was cooled to room temperature, it was diluted with benzene and filtered, and then the filtrate was washed with water. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 50 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to obtain 2.21 g (yield: 50%) of the title compound as an oil.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:29]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)NC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Product: CC(C)NC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-isopropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-isopropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with isopropylisocyanate in a manner analogous to that described in Example 8.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCCCCCC>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: COc1ccccc1
Solvent: CCCCCCC
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 142 °C
Reaction time: 0.03 h

Procedure:
To a 22-L reactor was charged compound 7 (650 g, 1.82 mol), anisole (3.25 L, 5 vol, anhydrous) and benzylamine (600 mL, 0.92 vol, 3 equiv). The batch (approximately 18° C.) was heated to 142±5° C. over 1 hour 44 minutes, with dissolution occurring at 30° C. The batch was maintained at 142±5° C. for 69 hours 30 minutes at which point HPLC analysis indicated that compound 7 was 0.9% by conversion (specification ≦1.7% by conversion). The batch was cooled to 45-50° C. over 5 hours 12 minutes (to aid cooling the nitrogen flow was increased once the batch was approximately 72° C.). At that temperature range, the batch was poorly stirring and on mixing, the batch temperature increased to 52° C. It was >50° C. for ≦15 minutes. The batch was aged for 2 hours 2 minutes once initially <50° C., then n-heptane (9.75 L, 15 vol, 99%) was added to the batch over 1 hour 56 minutes, maintaining the batch temperature at 45-50° C. The heating was then discontinued and the batch cooled to 25° C. over 10 hours 32 minutes and then to approximately 20° C. over 20 minutes. The total time the batch was maintained ≦25° C. was 4 hours 50 minutes (2 hours 47 minutes at approximately 20° C.). The batch was filtered under suction via a 24-inch polypropylene filter funnel (fitted with a PTFE cloth) and the reactor rinsed with anisole/n-heptane (1.3 L, 4:1) and the rinse transferred to the cake. The cake was then washed successively with two portions of n-heptane (1.3 L, 0.65 L). The total filtration time was 39 minutes. The batch (net wet weight 1004 g of KX2•391) was transferred to three glass trays and placed into a vacuum oven set at 50° C. and dried to constant weight over 96 hours 26 minutes.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].O.[OH-].[Li+].O.Cl>C(O)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-[[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]thio]propanoate (1.16 g, 3.4 mmole) from Example 5 in absolute ethanol (20ml) was added lithium hydroxide hydrate (0.2g, 4.8 mmole). Water was added until the solution became cloudy and the mixture was then stirred for 20 hours Additional lithium hydroxide hydrate (0.75 g, 17.9 mmole) was added and the mixture was stirred for another two hours. The mixture was poured into 0.5 N hydrochloric acid (75 ml) and extracted with diethyl ether (100 ml in two portions). The ether extract was dried over magnesium sulfate, filtered, and concentrated in vacuo to a solid. Recrystallization from hexane gave the title compound, m.p. 110°-113°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31].C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[C:22]([N+:30]([O-:32])=[O:31])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 16 h
Yield: 59.24 %

Procedure:
A stirred solution of 2-fluoro-4-iodoaniline (3.64 gm, 15.37 mmol) in dry THF (100 ml) under nitrogen was cooled to −78° C. and a solution of 1.0 M lithium hexa methyl disilazide (LiN(SiMe3)2) “LHMDS” (15.37 ml, 15.37 mmol) was added slowly. This reaction mixture was kept stirring at −78° C. for another hour and then 2,3,4,6-tetrafluoronitrobenzene was added. The reaction mixture was allowed to warm to room temperature and stirring continued for another 16 hours. Ethyl acetate (200 ml) was added to the reaction mixture and was washed with water. Organic layer was dried over sodium sulfate and further purified by column chromatography to provide yellow solid (3.75 gm, yield: 59.24%). M−H+: 410.9. 1H NMR (DMSO, 300 MHz): 6.85 (t, 1H); 7.38 (d, 1H); 7.62 (m, 2H); 8.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.Cl>>[ClH:1].[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([NH:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[N:7][CH:6]=1
Reactant: Cc1cccc(N)c1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Product: Cc1cccc(Nc2ncnc3[nH]ccc23)c1

Procedure:
Following the procedure described in Example 1, the title compound was prepared from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and m-toluidine (34%). HRMS: Calcd. 225.1140, Found 225.1131; anal. RP18-HPLC RT: 3.45 min; HCl salt MP: 219° C.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[CH:1]1([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:20][NH:27][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](C2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1C1CCCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Cis-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.644 g, 4.84 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.500 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.297 mL, 4.84 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (21 mL, 126.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (814 mg, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.83-0.98 (m, 2H), 1.01-1.16 (m, 3H), 1.25-1.40 (m, 1H), 1.50-1.88 (m, 6H), 1.95-2.13 (m, 3H), 2.88-3.07 (m, 2H), 3.70 (s, 3H), 3.79-3.89 (m, 1H), 3.95-4.07 (m, 1H), 5.70 (s, 1H). MS m/z 309 (M+H)+
Reaction SMILES: [Br:1]Br.O.[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[CH:6]=1>CC(O)=O>[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[C:6]=1[Br:1]
Reactant: BrBr
Reactant: N#Cc1cc(F)c(N)cc1F
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(F)c(N)c(Br)c1F
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 1.65 mL of Br2, 2 mL of H2O and 5 g of 4-amino-2,5-difluorobenzonitrile in 50 mL of AcOH is stirred at 20°-25° for 16 hours. The solvents are removed in vacuo and the residue partitioned between 100 mL of H2O and 3×200 ml of CH2Cl2. The CH2Cl2 extracts are washed with H2O, saturated NaHCO3, H2O (100 mL each), dried with Na2SO4 and evaporated in vacuo to give 6.89 g of crude 4-amino-3-bromo-2,5-difluorobenzonitrile. This is purified by dry-column chromatography using SiO2 to give 5.38 g (71% yield). Recrystallization from CH2Cl2 /hexane affords analytically pure material, m.p. 106°-108° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14]2)(=O)=O)=CC=1.C1OCCOCCOCCOCCOCCOC1.[K].[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12>CN(C=O)C>[O:48]=[C:46]1[C:45]2[C:44](=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:43](=[O:53])[N:47]1[CH2:12][C:13]1([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:14][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(NC(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of {1-[(tert-butoxycarbonyl)amino]cyclopropyl}methyl 4-methylbenzenesulfonate (100 g, 293 mmol) in DMF (1000 mL) was added 18-crown-6 (76.8 g, 291 mmol) and phthalimide potassium salt (80.5 g, 435 mmol). The reaction mixture was heated to 50° C. After 3 hours, the reaction mixture was cooled to ambient temperature, quenched with cold water (2000 mL), and filtered to afford crude solids. The solids were washed with petroleum ether (3×200 mL) and dried under reduced pressure to afford tert-butyl {1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]cyclopropyl}carbamate. The material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:6]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2nn(CCN3CCCCC3)cc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
4-Nitroindazole (1.00 g, 6.14 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was added. The mixture was stirred for 30 minutes and then 1-(2-chloro-ethyl)-piperidine hydrochloride (1.73 g, 9.40 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, the mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo to remove N,N-dimethylformamide and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.37 (m, 2 H) 1.45 (m, 4 H) 2.42 (m, 4 H) 2.85 (t, J=6.44 Hz, 2 H) 4.66 (t, J=6.61 Hz, 2 H) 7.49 (m, 1 H) 8.19 (m, 2 H) 8.91 (s, 1 H); MS (DCI/NH3) m/z 275 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>>[F:25][C:24]([F:27])([F:26])[S:21]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1)(=[O:22])=[O:20]
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CCCC3)c12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CCCC3)c12

Procedure:
This compound was prepared by treating (4-hydroxy-8-methylnaphthalen-1-yl) (pyrrolidin-1-yl)methanone (above step-2 intermediate) with Tf2O by following the similar procedure as described in Step-8 of Intermediate-22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:10](OC(OCC)OCC)C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[CH:10][NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: Fc1ccc2nc[nH]c2c1
Temperature: 150 °C

Procedure:
To the solution of 4-fluoro-benzene-1,2-diamine (10 g, 79.4 mmol) and triethylorthoformate (117 mL, 793 mmol) was added few drop of ethanol and the reaction mixture was refluxed at 150° C. overnight. The reaction mixture was concentrated and the residue was directly taken to the next step. [M+H]=137.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:31]#[N:32]>O1CCCC1.C(OCC)(=O)C.[Cu]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>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:31]#[N:32])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (180 mg, 0.094 mmol), tetrakis(triphenyphosphine)palladium(0) (5.4 mg, 0.047 mmol) and copper(I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture at reflux overnight, additional copper(I) cyanide (420 mg, 4.7 mmol), copper(I) iodide (107 mg, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 0.28 mmol) were added and the reflux was continued for 1 hour. The reaction mixture turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 410 mg of the title compound as a crude yellow solid.