Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[C:10]([CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])(=O)[CH3:11]>C(O)CCC>[NH2:8][C:7]1[N:6]([NH2:5])[C:14](=[O:15])[C:13]([CH2:18][CH2:17][OH:16])=[C:10]([CH3:11])[N:9]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: CCCCO
Product: Cc1nc(N)n(N)c(=O)c1CCO
Yield: 65.2 %

Procedure:
A mixture of 13.6 g of aminoguanidine bicarbonate and 12.8 g of 2-acetyl butyrolactone in 80 ml of n-butanol was heated at reflux until a clear solution was obtained. This solution was cooled, evaporated to dryness in vacuo and the residue was triturated with 200 ml of a 50/50 ether-chloroform mixture, giving 12 g of the desired intermediate, mp 126°-135° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:19]([OH:30])[CH2:18][CH2:17]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C@@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:19]([O:30][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:18][CH2:17]2
Reactant: COc1ccc2c(c1)CC[C@@H](O)[C@@H]2c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@@H]2c1ccccc1
Yield: 108.1 %

Procedure:
A solution of para-toluenesulfonyl chloride (1.8 g, 9.43 mmol) in dichloromethane (10 mL) was added to a solution of trans-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol 29 (2.0 g, 7.86 mmol), N,N-diisopropylethylamine (4.8 mL, 27.5 mmol) and 4-dimethylaminopyridine (1.15 g, 9.43 mmol) in dichloromethane (40 mL) at 0C. The resultant solution was stirred at ambient temperature for 16 h. The solution was washed successively with 1 N aqueous sodium hydroxide (×2) and a saturated aqueous solution of sodium chloride, then dried over sodium sulfate. The solvent was evaporated in vacuo to give crude trans-6-methoxy-1-phenyl-2-(4-methylbenzenesulfonyl)oxy-1,2,3,4-tetrahydronaphthalene 30 (3.47 g), as a pale yellow solid which was used without further purification in the subsequent step. 1H NMR(CDCl3) δ1.90-2.04 (m, 1H), 2.14-2.24 (m, 1H), 2.42 (s, 3H), 2.83-3.07 (m, 2H), 3.77 (s, 3H), 4.16 (d, 1H), 4.80-4.87 (m, 1H), 6.60-6.67 (m, 3H), 6.82-6.90 (m, 2H), 7.13-7.23 (m, 5H), 7.58 (d, 2H).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:35])[C@H:24]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:35])=[O:22])[CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](COCc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to O-benzylserine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].Cl[C:21]1[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:21]1[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: FC(F)(F)c1nnc(Cl)s1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1nnc(C(F)(F)F)s1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 253a) was reacted with 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (CAS Reg. No. 53645-98-0) in a shaking reactor at 55° C. for 12 h to give the title compound as orange oil. MS (ESI): m/z=456.0 [M+H]
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][N:20]1[C:26](=[O:27])[C@@H:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][O:23][C:22]2[C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=[CH:39][C:21]1=2>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:28][C@H:25]1[CH2:24][O:23][C:22]2[C:36]([C:40]([F:42])([F:41])[F:43])=[CH:37][CH:38]=[CH:39][C:21]=2[N:20]([CH2:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][C:9]=2[CH3:8])[C:26]1=[O:27]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2c1cccc2C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)COc2c1cccc2C(F)(F)F
Yield: 100 %

Procedure:
TFA (533 μl) was added to a solution of (S)-tert-butyl 5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (71 mg, 142 μmol) in DCM (2 mL) at 0° C. After 2.5 h the mixture was concentrated and the residue azeotroped with MeCN to afford (S)-3-amino-5-((2-methylnaphthalen-1-yl)methyl)-9-(trifluoromethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (73 mg, 100%) which was used without purification.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([S:10](CCC(OC)=O)(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.C[O-].[Na+].CC([O-])=O.[Na+].[NH2:27]OS(O)(=O)=O>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([C:7]([S:10]([NH2:27])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1
Reactant: COC(=O)CCS(=O)(=O)C(C)(C)c1ncc(Br)s1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(c1ncc(Br)s1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
The product of Step 4 (2.50 g, 7.02 mmol) was taken up in THF (80 mL) at room temperature, and NaOMe (25% in MeOH, 1.52 g, 7.02 mmol) was added. After 30 min at room temperature, the suspension was evaporated to dryness, providing a white solid. The solid was taken up in water (50 mL), and a solution of NaOAc (3.17 g, 38.6 mmol) and hydroxylamine-O-sulfonic acid (3.97 g, 35.1 mmol) in water (25 mL) was added while cooling the reaction (0° C.). The reaction was vigorously stirred at room temperature overnight (a white solid precipitated after 15-30 min). The reaction was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The resulting white residue was triturated with CH2Cl2 and filtered to provide 2-(5-bromo-1,3-thiazol-2-yl)propane-2-sulfonamide (1.58 g, 79%) as a white powder. ESI: [M+H]+ m/z 284.9/286.9.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:35])[N:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[O:34])N(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>C1COCC1.CCCCCC>[CH3:13][O:14][C:15]([N:16]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](=[O:34])[CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]1=2)=[O:35]
Reactant: COC(=O)N(c1ccccc1C)c1ccccc1C(=O)N(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Diisopropylamine (11.66 g, 0.115 mol, 1.2 eq.) is dissolved in THF (150 mL) and the solution is cooled down to −10° C. A solution of n-Butyllithium in hexane (72 mL of a 1.6 M solution, 1.2 eq.) is added slowly in order to keep the temperature below 0° C. (40 min). A solution of (2-dimethylcarbamoyl-phenyl)-o-tolyl-carbamic acid methyl ester (30.2 g, 0.096 mol, 1 eq.) in THF (80 mL) is added in 45 min. to the obtained solution. The reaction mixture is stirred for 1 hour at −5° C. before quenching by addition of water (30 mL). The mixture is concentrated in vacuum and water (220 mL) and ethylacetate (220 mL) are added to the oily residue. The phases are stirred rapidly before letting them separate. The organic phase is washed with aqueous sulfuric acid (300 mL of 1-M solution) and twice with water (300 mL). The organic phase is evaporated to dryness and delivers 23.0 g (89.5% yield) of the title compound as an orange oil that solidifies on standing.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(CCCN)c1ccccn1
Reactant: CSc1ncc(Cc2ccccc2Cl)c(=O)[nH]1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccccc2Cl)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.74 g) and 2-methylthio-5-(2-chlorobenzyl)pyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 28 hr. After stripping, the residue was recrystallised twice from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino)propylamino]-5-(2-chlorobenzyl)pyrimid-4-one 0.5H2O, 0.87 g (59%) mp 47°-49° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH:16][C:17]([C:19]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=2)=[O:18])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC.CN(C=O)C>CCOC(C)=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>[CH3:14][C:11]1([CH3:15])[CH2:12][CH2:13][C:8]([C:6]2[C:5]([NH:16][C:17]([C:19]3[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=3)=[O:18])=[CH:4][CH:3]=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[N:7]=2)=[CH:9][CH2:10]1
Reactant: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a round bottom flask containing 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in Example 56, step (c), 32 mg, 0.060 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and tributyl-(1-ethoxy-vinyl)-stannane (30 mg, 0.080 mmol) was added DMF (0.7 mL) and the resultant solution was allowed to stir at 100° C. overnight. The reaction was diluted with EtOAc (25 mL), washed with water (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the residue by preparative TLC (20% EtOAc-hexanes) afforded 12 mg (43%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C28H39N5O3Si, 522.2 (M+H). found 522.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2O.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][N:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cnc2cnc(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc2cnc(F)cc2c1Cl
Temperature: 0 °C
Yield: 92 %

Procedure:
To 10 g of 6-fluoro-4-hydroxy-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere in 150 mL of methylene chloride was added 24 mL of oxalyl chloride followed by 0.4 mL of N,N-dimethyl formamide. After two hours at reflux, an additional 5 mL of oxalyl chloride and 0.3 mL of N,N-dimethyl formamide was added. After an additional hour at reflux, the reaction was poured into ice-water and solid potassium carbonate was added carefully to a pH of about 8. The chloroform layer was washed with brine, dried with sodium sulfate, and stripped to give a crude product. This material was further purified by passing it through a plug of silica gel with chloroform and recrystallizing from a mixture of chloroform and hexanes to give 10 g (92%) of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile as a yellowish solid: melting point 150-155° C.; mass spectrum (m/e): M+H2O-Cl 190.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:2].[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])([O-:29])=[O:28]>C(Cl)Cl.N>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:17]=[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:32]([C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[N+:27]([O-:29])=[O:28])=[O:33])[CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH3:26]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCN(CC)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Agent: N
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(NC2CCN(C(=O)c3ccccc3[N+](=O)[O-])CC2)c2ccccc2n1

Procedure:
A solution of N2-(3-(diethylamino)propyl)-N4-(piperidin-4-yl)quinazoline-2,4-diamine (55 mg, 0.154 mmol) and 2-nitrobenzoyl chloride (57 mg, 0.309 mmol) and TEA (43 ul, 0.309 mmol) in CH2Cl2 was stirred at room temperature for 1 hour. The crude reaction was directly loaded on the silica gel column and isolated the product using 10% NH3 ca. 7 N MeOH in CH2Cl2 and 90% CH2Cl2 solution as eluent to gain a yellow oil.
Reaction SMILES: CN(C=O)C.[N:6]1([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH:17]([NH:21][C:22](=[O:43])/[C:23](=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([N:35]4[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]4)=[C:31]([O:41][CH3:42])[CH:30]=2)/[CH2:24][CH2:25][CH2:26]Cl)[CH2:16][CH2:15]3)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[H-].[Na+].O>C(OCC)(=O)C>[CH3:42][O:41][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1)/[CH:28]=[C:23]1/[C:22](=[O:43])[N:21]([CH:17]2[C:18]3[C:14](=[CH:13][C:12]([N:6]4[CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)[CH2:26][CH2:25][CH2:24]/1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2CCc3cc(N4CCOCC4)ccc32)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(/C=C2\CCCN(C3CCc4cc(N5CCOCC5)ccc43)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
To a DMF (5.0 mL) solution of ((E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (5-morpholin-4-yl-indan-1-yl)amide (2.80 g), sodium hydride (40% mineral oil content, 267 mg) was added at 0° C., and the reaction solution was agitated for 15 minutes. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By purifying the obtained residue by silica gel chromatography (elution solvent:a heptane-ethyl acetate system, ethyl acetate-ethanol system), 2.12 g of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-1-(5-morpholin-4-yl-indan-1-yl)piperidin-2-one racemate was obtained. Next, this compound (140 mg) was separated in CHRIALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cm×25 cm mobile phase; ethanol), and the title optically active substance with a retention time of 14 minutes (64 mg; >99% ee) and the title optically active substance with a retention time of 16 minutes (58 mg; >97% ee) were obtained. The physical properties of the title optically active substance with a retention time of 14 minutes are as follows.
Reaction SMILES: ClC1C=C([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=C(Cl)C=1.Br[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:20][C:21]=1[F:26]
Reactant: Fc1cc(Br)ccc1Cl
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Product: O=C(Cc1ccccc1)c1ccc(Cl)c(F)c1
Yield: 18.2 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 4-bromo-1-chloro-2-fluorobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to afford Intermediate 16 (200 mg, yield 18.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10](I)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:11]=12
Reactant: Nc1ncnc2c1c(I)nn2-c1ccnc(Cl)c1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(-c3ccnc(Cl)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 50 %

Procedure:
A suspension of 1-(2-chloro-4-pyridyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.95 g, 0.00256 mol) in dimethoxyethane (30 mL) and water (60 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (1.14 g, 0.00281 mol), sodium carbonate (0.68 g, 0.00640 mol) and tetrakis (triphenylphosphine)palladium (0) (0.30 g, 0.00026 mol) at 80° C. for 3 days. The solid was filtered and washed with water. The solid was triturated with ethyl acetate (75 mL) for 6 hours and filtered, washing with ethyl acetate (20 mL). The solid was then triturated with methanol (75 mL) for 6 hours and filtered, washing with methanol (20 mL). The solid was dried in vacuo to give crude N2-{4-[4-amino-1-(2-chloro-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.672 g, 0.00128 mol) as a tan solid:
Reaction SMILES: [N:1]([C:4]1[C:5]([C:9]([O:11]CC)=O)=[CH:6][S:7][CH:8]=1)=[C:2]=[S:3].[F:14][C:15]([F:26])([F:25])[CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>C(#N)C.C(O)C>[S:3]=[C:2]1[NH:1][C:4]2=[CH:8][S:7][CH:6]=[C:5]2[C:9](=[O:11])[N:22]1[C:21]1[CH:23]=[CH:24][C:18]([O:17][CH2:16][C:15]([F:14])([F:25])[F:26])=[CH:19][CH:20]=1
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: CCOC(=O)c1cscc1N=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: O=c1c2cscc2[nH]c(=S)n1-c1ccc(OCC(F)(F)F)cc1
Yield: 86 %

Procedure:
Ethyl 4-isothiocyanatothiophene-3-carboxylate (1.1 g) and 4-(2,2,2-trifluoroethoxy)aniline (0.99 g) were dissolved in acetonitrile (40 ml), and the solution was heated under reflux for 1 hr, and allowed to be cooled. Potassium tert-butoxide (1.27 g) was dissolved in ethanol (15 ml), and the solution was poured into the reaction mixture at room temperature. The reaction mixture was heated under reflux for 10 min, allowed to be cooled, and concentrated under reduced pressure. The obtained brown residue was dissolved in ethanol (10 ml), and the solution was poured into 0.3M hydrochloric acid (35 ml) under ice-cooling. The resulting precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (40 ml). The solution was diluted with ethyl acetate (80 ml). This organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a solid. This solid was washed with a mixed solvent of tetrahydrofuran/isopropyl ether (1/10) to give the title compound (1.59 g) as a solid.
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6]C[CH:4]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)#N.[OH-:18].[K+].[CH2:20]([OH:23])[CH2:21]O>O.[OH-].[Na+]>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH:4]2[CH2:3][CH2:8][CH2:7][CH2:6][CH:21]2[C:20]([OH:23])=[O:18])[CH:15]=[CH:14][CH:13]=1
Reactant: OCCO
Reactant: [OH-]
Reactant: COc1cccc(CC2CCCCC2C#N)c1
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cccc(CC2CCCCC2C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of 1-cyano-2-[(3-methoxyphenyl)methyl]-cyclohexane (3.60 g) and potassium hydroxide (2.82 g) in ethyleneglycol (12.3 ml) was refluxed for 5 hours, cooled to room temperature, and diluted with water and 5% sodium hydroxide aqueous solution. The resulting mixture was washed three times with diethyl ether, acidified with conc. hydrochloric acid, and extracted with diethyl ether. The extract was dried over magnesium sulfate and evaporated in vacuo to give 2-[(3-methoxyphenyl)-methyl]cyclohexanecarboxylic acid (3.11 g) as an oil.
Reaction SMILES: [CH3:1]N(C=O)C.[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:16])[CH:8]=1.C(=O)([O-])O.[K+].IC>O>[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:1])=[O:12])=[C:9]([OH:16])[CH:8]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(F)cc1O
Reaction time: 0.17 h

Procedure:
1.1 50 ml of DMF are added under argon to 6.0 g of 4-fluoro-2-hydroxybenzoic acid and 4.52 g of potassium hydrogencarbonate, and the mixture is stirred for 10 minutes. 3.05 ml of iodomethane are added dropwise, and the mixture is stirred at 40° for 3 hours. The mixture is poured into 150 ml of water and subjected to conventional work-up, giving 6.48 g of methyl 4-fluoro-2-hydroxybenzoate (“1a”).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]
Reactant: CCCCOC(=O)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), butyl salicylate (388 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and at 140° C. for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (106 mg, yield 57%).