Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23][CH3:24])[C:16]=1[NH2:17])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:24])=[O:9])[C:16]=1[NH2:17])([CH3:14])[CH3:13]
Reactant: CSCc1cccc(C(C)C)c1N
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cccc(CS(C)=O)c1N
Reaction time: 1.5 h
Yield: 70 %

Procedure:
12.9 g (52.3 mmol) of m-chloroperbenzoic acid (70% purity) were added over a period of 15 minutes to a suspension of 10.21 g (52.3 mmol) of 2-isopropyl-6-methylthiomethylaniline [prepared as described in step (i) above] and 5.31 g (50 mmol) of sodium carbonate in 200 ml of methylene chloride, whilst ice-cooling. The reaction mixture was stirred for 1.5 hours at the same temperature, after which it was diluted with methylene chloride, and the diluted mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, with an aqueous solution of sodium sulfite and with water, in that order. The solvent was then removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of diethyl ether and diisopropyl ether, to give 7.74 g of the title compound as a first crop. The mother liquor was then concentrated by evaporation under reduced pressure, and the concentrate was repeatedly recrystallized from the same solvent to give a further 0.75 g of the title S-oxide derivative. The total yield was 8.49 g (yield 77%). The title compound melted at 91°-91.5° (after recrystallisation from a mixture of methylene chloride and diisopropyl ether).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1>>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, white solid (74 mg, 94%), MS (ISP) m/z=316.5 [(M+H)+], mp 240.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:26][CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using ((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester and benzyl 2-bromoethyl ether, the title compound was prepared in the same manner as described for example 1a. White crystals, mp. 132-134° C. (84%). MS: m/e=459(M+H+), mp 133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](Cl)(Cl)Cl)[CH:5]=[CH:4][N:3]=1.NC1C=C(C)C=CN=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:23](=[O:24])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:25])[CH:7]=1
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccnc(N)c1
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1

Procedure:
A process for the preparation of 2-amino-4-trichloromethylpyridine of the formula I, wherein 2-amino-4-picoline is reacted with phthalic anhydride to give 4-methyl-2-phthalimidopyridine, the latter is chlorinated and the product is hydrolyzed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CCCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1CN1CCNCC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-6-propoxy-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0705 g, 0.136 mmol) in methylene chloride (7 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (7 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate (14 mL), and the precipitated solid was collected by filtration. The resulting solid was washed with water, and then further washed with acetonitrile to obtain (Z)-2-[(1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)-6-propoxybenzofuran-3(2H)-one (0.0306 g, 53%).
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[F:30])[CH2:17][CH2:16]1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.5 %

Procedure:
4N Hydrogen chloride/ethyl acetate solution (10.0 ml, 40.0 mmol) was added to a solution of 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (compound of Reference Example 14; 2.50 g, 7.68 mmol) in ethyl acetate (10 ml) under ice cooling, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was adjusted to pH=9 by addition of saturated aqueous sodium hydrogencarbonate, and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with water to give the title compound (0.563 g, 37%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:19]>Cl.C(O)C>[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:19]=[CH:15][C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: CN(N)c1ccccc1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: CCO
Product: CN(N=Cc1c2ccccc2cc2ccccc12)c1ccccc1

Procedure:
3.1 g of anthracene-9-aldehyde and 1.8 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude anthracene-9-aldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethyl acetate. The yield was 2.3 g (48.9%) of yellow needle-like crystals which melt at 162.0°-162.5° C.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:16]([NH:20][NH2:21])([CH3:19])([CH3:18])[CH3:17]>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[S:15])[NH:21][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CC(C)(C)NN
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=S)NNC(C)(C)C)CCCCC1

Procedure:
To 8.7 grams (.0376 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 5° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added dropwise 4.36 grams (.0376 moles) of a 76% aqueous solution of t-butylhydrazine. The reaction was very exothermic and rapid and was complete almost immediately after the addition was complete. Pentane was added to slurry up the solids and the mixture stirred for 1 hour at room temperature. The pentane was stripped from the reaction mixture to leave a yellow solid weighing 11.3 grams (94.5% crude yield). The product melted at 120°-122° C. and the infrared spectrum of the product had sharp strong bands at 1540 and 1520 cm-1 and sharp NH bands at 3150 and 3280 cm-1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:18][CH:17]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:20][CH:21]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Yield: 77.8 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[H-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]2
Reactant: O=C1NCc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C

Procedure:
5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before tert-butyl bromoacetate (92 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO3 (10 mL) was carefully added. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C14H16BrNO3 [M+Na]+: 348. Found: 348.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([N:16]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:14]([F:19])[CH:13]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N1CCCC1

Procedure:
A mixture of 2.3 g (8.8 mmoles) of 4-(1-adamantyloxy)-2-fluoroaniline, 1.90 g (8.80 mmoles) of 1,4-dibromobutane, and 2.68 g (19.4 mmoles) of K2CO3 in deaerated absolute ethanol (25 ml) is refluxed for twenty-four hours. The solvent is evaporated, and the residue taken up in methylene chloride (125 ml) and water (125 ml). The methylene chloride layer is washed with 2×125 ml of water, and the combined aqueous portions are extracted with methylene chloride (50 ml). The combined methylene chloride layers are dried and concentrated. The crude product is chromatographed by high pressure liquid chromatography on a 2.54×109 cm column at approximately 40 psi, eluting with 0.5% acetone in methylene chloride and collecting 200 ml fractions. Fraction 3 contains 1.5 g of tan solid, m.p. 99.0°-105.9° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23])[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[N:6]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1)[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CN(c1ccncc1F)n1cc(C)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cn(N(CCO)c2ccncc2F)c2ccccc12
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To N-(3-fluoro-4-pyridinyl)-N-(3-methyl-1H-indol-1-yl)glycine ethyl ester (5.0 g) in 100 ml of tetrahydrofuran cooled to ice bath temperature was added lithium aluminum hydride (1M solution in tetrahydrofuran, 30 ml) via syringe. The reaction was stirred for 0.5 hour. The mixture was quenched with NH4Cl and extracted three times with ethyl acetate. The organics were combined, washed with sat. NaCl and dried (MgSO4). After filtering, the solvent was evaporated to yield a solid (3.9 g) which was eluted with 50% ethyl acetate/dichloromethane on a silica gel column via high pressure liquid chromatography (HPLC). The desired fractions were evaporated to yield 3.7 g of a solid, m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[C@H:11]2[O:16][C@@:17]([O:24][CH3:25])([CH3:23])[C@:18]([O:21][CH3:22])([CH3:20])[O:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:28])[C@H:11]2[O:16][C@@:17]([O:24][CH3:25])([CH3:23])[C@:18]([O:21][CH3:22])([CH3:20])[O:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CO[C@@]1(C)O[C@@H]2[C@@H](CO)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Solvent: ClC(Cl)Cl
Product: CO[C@@]1(C)O[C@@H]2[C@@H](CCl)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Yield: 83.8 %

Procedure:
To a solution of ((2S,3S,4aR,8R,8aR)-6-benzyl-2,3-dimethoxy-2,3-dimethyloctahydro-[1,4]dioxino[2,3-c]pyridine-8-yl)methanol (1) (2.5 g, 7.1 mmol) in chloroform (35 mL) was added thionyl chloride (1.3 mL, 18 mmol). The resulting mixture was heated at reflux for 4-8 hours until reaction was judged complete by TLC (98:2 CH2Cl2/2-PrOH). Solvent and excess reagent were evaporated in vacuo and the residue was chromatographed (98:2 CH2Cl2/2-PrOH) to give the title compound (2.2 g, 85%). Product was characterized via HPLC/MS (MH+=369). Purity was judged as >95%.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32]2[C:27](=[CH:28][C:29]([NH2:38])=[CH:30][CH:31]=2)[C:26]1=[O:39].O>CN(C=O)C>[CH3:24][N:25]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32]2[C:27](=[CH:28][C:29]([NH:38]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:30][CH:31]=2)[C:26]1=[O:39]
Reactant: CN1C(=O)c2cc(N)ccc2C(C)(C)C1=O
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2cc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)ccc2C(C)(C)C1=O
Temperature: 120 °C

Procedure:
Prepared from 3-(1-ethoxy-1-phenylmethylidene)-5-nitro-2-indolinone and 1.5 equivalents of 2-methyl-7-amino-4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline, melting point 169-171° C., in DMF by heating to 120° C. for 1 hour, pouring into water, filtering and washing the precipitate with MeOH and ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[N:34]([CH3:35])[N:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[N:34]([CH3:35])[N:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(C(F)(F)F)nn3C)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(C(F)(F)F)nn5C)c34)n(-c3ccccc3)c(=O)c12
Yield: 65.6 %

Procedure:
(S)-5-Methyl-2-(1-((5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (38 mg, 0.04 mmol, 66% purity) was treated with trifluoroacetic acid (760 μl, 9.86 mmol) and a solution of ammonia (7N in methanol, 760 μl, 5.32 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (reverse phase, 0% to 100% water-methanol/acetonitrile 1:1) to obtain 14 mg (69% yield) of the title compound.
Reaction SMILES: [C:1]12([C:14]([O:16]C)=[O:15])[CH2:9][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2>C(O)C.O>[CH3:13][O:12][C:10]([C:5]12[CH2:9][C:1]([C:14]([OH:16])=[O:15])([CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2)=[O:11]
Reactant: COC(=O)C12CCCC(C(=O)OC)(CCC1)C2
Solvent: O
Solvent: CCO
Product: COC(=O)C12CCCC(C(=O)O)(CCC1)C2
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A solution of dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate (8.32 g, 36.8 mmol) and Ba(OH)2.8H2O (5.80 g, 18.4 mmol) in ethanol (40 mL) and H2O (10 mL) was refluxed overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was added diluted with water (100 mL) and extracted with diethyl ether (3×200 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated under reducer pressure to recover starting material as an orange oil. The aqueous phase was adjusted to pH 1˜2 with 2N aq. HCl, and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1.8 g (67%) of 5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic acid as a white solid. ESI-MS m/z: 213 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:22](I)[CH:23]=[CH2:24].CCOC(C)=O>CN(C=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=2[N:3]1[CH2:24][CH:23]=[CH2:22]
Reactant: COC(=O)c1cnc2ccc(=O)[nH]c2c1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ncc(C(=O)OC)cc21
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
A solution of methyl 6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (1.963 g, 5.36 mmol) in DMF (32 ml) was treated with K2CO3 (2.95 g, 21.3 mmol), stirred for 10 mins and then treated with allyl iodide (0.535 ml, 5.88 mmol), heated for 7 h at 75° C., further allyl iodide (0.15 ml, 0.89 mmol) was added and the reaction heated for a further 2 h. The reaction was treated with EtOAc, washed with water three times. The combined aqueous phases were then re-extracted with EtOAc and this washed with water twice. The combined organic phases were dried, evaporated and the residue was subjected to column chromatography on silica gel using a 1:1 EtOAc:hexane gradient to provide the desired compound (0.809 g, 62%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[C:8]([F:15])[C:7]=1[F:16])[CH2:2][CH2:3][CH3:4].C(O)(=[O:19])C.OO.S([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:19])=[C:8]([F:15])[C:7]=1[F:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(B(O)O)c(F)c1F
Reactant: CC(=O)O
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(O)c(F)c1F
Reaction time: 2 h

Procedure:
The compound (23) (40.0 g) and acetic acid (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and hydrogen peroxide (31% aqueous solution; 40.4 ml) was added dropwise in the temperature range of 25° C. to 30° C., and the stirring was continued for another 2 hours. Then the reaction mixture was poured into a vessel containing sodium hydrogen sulfite solution (100 ml) and ethyl acetate (300 ml), and mixed. Then the mixture was allowed to separate into organic and aqueous phases, and the extraction was carried out. The organic phase obtained was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure, giving 31.7 g of 4-butoxy-2,3-difluorophenol (24). The yield based on the compound (23) was 90.2%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][N:19]=[C:18]([N:27]([CH3:29])[CH3:28])[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([N:27]([CH3:29])[CH3:28])[N:17]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(N(C)C)nc1O[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ncc(C(=O)O)c(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 15 mL of ethanol was dissolved 2.675 g of N-tert-butoxycarbonyl-trans-4-[5-ethoxycarbonyl-2-(dimethylamino)pyrimidin-4-yloxy]cyclohexylamine (the compound of Reference Example 9-50 prior to deprotection treatment), 3.27 mL of an aqueous 3N-sodium hydroxide solution was added thereto at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with water, and then, citric acid was added thereto until the solution became neutral. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to obtain 2.015 g of N-tert-butoxycarbonyl-trans-4-[5-carboxy-2-(dimethylamino)pyrimidin-4-yloxy]cyclohexylamine. (2) The compound obtained in the above (1) was used as a starting material and reacted with a starting amine compound in the same manner as in Reference Example 11-1. The resulting compound (hydrochloride) was made into an aqueous solution, and the solution was treated with potassium carbonate and extracted with chloroform to obtain a free form.