Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35]Br.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([F:40])=[C:32]([F:31])[CH:33]=3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(F)c(F)c2)c1=O
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 3,4-difluorobenzyl bromide (256 uL, 2.0 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from ethanol-water gave the title compound (138 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.12 (br. s., 1 H), 7.28-7.52 (m, 2 H), 7.05-7.23 (m, J=5.43, 3.16 Hz, 1 H), 4.96 (s, 2 H), 4.63 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.25 (q, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.63 (s, 3 H), 1.28 (q, J=12.97 Hz, 2 H), 1.11 (q, 1 H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH2:20][CH3:21])[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1.OO.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:1][N:2]1[C:6]2[C:7](=[O:8])[NH:9][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:10][C:5]=2[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: CCCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 58.8 %

Procedure:
1-Methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrazole-5-carboxamide (0.34 g, 0.99 mmol) was added to a stirred mixture of 30% hydrogen peroxide solution (1.0 ml), potassium carbonate (0.54 g, 3.92 mmol), water (10 ml) and ethanol (5 ml). The mixture was heated under reflux for 38 hours and then evaporated under vacuum. The residue was suspended in water (20 ml), then the suspension acidified with 2N hydrochloric acid and extracted with dichloromethane (3×20 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum. The resulting residue was chromatographed on silica gel (6 g), using a methanol in dichloromethane elution gradient (0-1% methanol), to give an oil, successive trituration of which with ether gave the required product as a white solid (0.19 g, 59%), m.p. 111°-114° C. Found: C,66.26; H,6.92; N,17.15. C18H22N4O2 requires C,66.23; H,6.80; N,17.17%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([O:33]C)=[O:32])=[N:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:13]([O:12][C:11]([NH:10][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([OH:33])=[O:32])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
A solution of methyl ester 20 (6.00 g, 8.21 mmol) in MeOH/THF/H2O (100 mL/100 mL/50 mL) was charged with NaOH (1.64 g, 41.1 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH of the solution was adjusted to 5 with 1 N HCl. The suspension was partitioned between CH2Cl2 (150 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×150 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 21 (5.50 g, 94%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.06-4.00 (m, 1H), 4.00-3.93 (m, 1H), 3.35 (t, J=7.3 Hz, 2H), 3.26-3.07 (m, 2H), 1.85-1.56 (m, 6H), 1.53-1.32 (m, 6H), 1.52 (s, 9H), 1.46 (s, 9H), 1.438 (s, 9H), 1.435 (s, 9H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:24])=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)C)(C)(C)C.Cl>CO>[Cl:24][C:15]1[N:16]=[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[O:11][CH2:10][CH2:9][N:7]([CH3:6])[C:13]=2[N:14]=1
Reactant: CN(CCOc1c(Cl)nc(Cl)nc1N1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CN1CCOc2c1nc(Cl)nc2N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
A mixture of [2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.50 mmol) and 4M HCl in methanol (10 mL) was stirred at RT for 1.5 hours then concentrated in vacuo and azeotroped with ethanol. The resultant residue was dissolved in methanol (10 mL) then treated with triethylamine (3.0 mL) and the mixture stirred at RT for 30 minutes before being concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-50% ethyl acetate in cyclohexane) affording 2-Chloro-8-methyl-4-morpholin-4-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (368 mg, 91% over 3 steps). LCMS: RT=2.94 min, [M+H]+=271/273.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.CN(C)[C:18]1[O:19][C:20](=[O:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1>C1(C)C(C)=CC=CC=1>[CH:1]([N:4]1[C:20](=[O:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[NH:23][C:18]1=[O:19])([CH3:3])[CH3:2]
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: CC(C)N
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: CC(C)n1c(=O)cc(C(F)(F)F)[nH]c1=O
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Isopropylamine (1.2 g, 20.3 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 6 mL) are added to a solution of 2-dimethylamino-4-trifluoromethyl-6H-1,3-oxazin-6-one (4.0 g, 19.2 mmol) in xylene (34 mL). The resultant reaction mixture is held at 100° C. for 3 hours, cooled, washed with 5 wt. % HCl (40 mL), and extracted with ethyl acetate. The combined organic extracts are concentrated and triturated with heptane. The solids are filtered and dried to give the title product as a yellow powder (2.3 g, 54% yield, mp 127°-129° C.) which is identified by 1H NMR (DMSO-d6) δ 6.11 (1H, s), 4.96 (1H, sp), 1.35 (6H, d) ; and 19F NMR δ -68.9 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:33][N:32]=[C:31]4[NH:39][CH:40]=[CH:41][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:33][N:32]=[C:31]4[NH:39][CH:40]=[CH:41][C:30]=34)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)Oc1cnc2[nH]ccc2c1N1CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(OC(C)C)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Yield: 60.8 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-isopropoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (30 mg, 0.051 mmol) in TFA (3 mL) was stirred for 30 minutes and then concentrated to dryness. The resulting residue was dissolved in minimal DCM (0.2 mL) and added to 2N HCl in ether. The resulting solid was filtered and dried under nitrogen to yield (S)-2-(4-chlorophenyl)-1-(4-(5-isopropoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (15 mg, 60% yield) hydrochloride as a solid. 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.23 (s, 1H), 8.56 (s, 1H), 7.99 (s, 1H), 7.51-7.47 (m, 2H), 7.44-7.39 (m, 3H), 6.69 (s, 1H), 4.76 (m, 1H), 4.43 (m, 1H), 3.85-3.50 (m, 7H), 3.47-3.40 (m, 1H), 3.35-3.27 (m, 1H), 3.23-3.15 (m, 1H), 3.05-2.98 (m, 1H), 1.28-1.20 (m, 12H); m/z (ESI pos) 484.4 (100%) [M].
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=O)=[CH:11][CH:10]=1.[C:30]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].CCOCC.O>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:38]([C:37]3[CH:39]=[CH:40][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[C:18]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)(C)c1ccc(-n2c(-c3ccc(Br)cc3)ccc2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 110 °C

Procedure:
TFA (0.6 mL, 7.79 mmol) was added to a mixture of the product from Example 39A (1.2335 g, 3.41 mmol) and 4-tert-butylaniline (0.8 mL, 5.07 mmol) in toluene (30 mL) and heated at 110° C. for 17 hours. The cooled reaction mixture was poured into ether/water and stirred until nice solid formed. The mixture was filtered to afford the title compound. 1H NMR (400 MHz, BENZENE-D6) δ 1.02 (s, 9H), 6.48 (d, J=3.8, 1H), 6.52 (d, J=3.8, 1H), 6.63 (d, J=8.5, 2H), 6.80 (d, J=8.5, 2H), 6.84 (d, J=8.9, 2H), 6.89 (d, J=8.5, 2H), 7.10 (d, J=8.5, 2H), 7.70 (d, J=8.9, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([CH2:20][N:21]1[CH2:26][CH2:25][C:24]([OH:35])([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([OH:19])[CH:14]([CH2:20][N:21]1[CH2:22][CH2:23][C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)([OH:35])[CH2:25][CH2:26]1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC2(O)CCN(CC3CCc4cc(OCc5ccccc5)ccc4C3=O)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CC3CCc4cc(OCc5ccccc5)ccc4C3O)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.8 %

Procedure:
(RS)-6-Benzyloxy-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-ylmethyl]-3,4-dihydro-2H-naphthalen-1-one (1.30 g, 2.77 mmol) in THF (15 ml) was added dropwise to a suspension of LiAlH4 (0.6 g, 15.5 mmol) in THF (20 ml) over 15 min (5-10° C.) and then stirred at RT for 2.5 hr. Distilled H2O (1 ml) and 4N NaOH (2 ml) followed by further H2O (2 ml), was added to quench the reaction and stirred vigorously 15 min., the mixture was then dried with Na2SO4, filtered and evaporated. The resulting crude liquid was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH—NH4OH (100:5:0.25) to afford the title compound as a white foam (0.75 g, 1.6 mmol, 57%), MS m/e=472.4 (M+H+).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.[CH3:21][O:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:5]1([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[S:3][C:2]([NH:1][C:28]([NH:27][C:25](=[O:26])[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22][CH3:21])=[O:29])=[N:6]1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: COc1ccccc1C(=O)N=C=O
Solvent: Cc1ccccc1
Product: COc1ccccc1C(=O)NC(=O)NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) was dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g), and 2-methoxybenzoylisocyanate (0.4 g) which is a starting compound was added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccs3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cccs4)n3n2)cc1
Yield: 41.7 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (Intermediate 61) (115 mg, 0.32 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.24 mL, 2.57 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(2-thienyl)imidazo[5,1-f][1,2,4]triazin-2-amine (45 mg) as a yellow solid. MS m/z 338 (M+1).
Reaction SMILES: C(OC[CH:6]1[CH:8]([C:9]([O:11][CH2:12]C)=[O:10])[C:7]1([CH3:15])[CH3:14])(=O)C.CC[C@@H]1N2C(N(C3C=CC(F)=CC=3)C(=O)[C@H]2CC2C3C(NC1=2)=CC=CC=3)=O.[OH-].[Na+].OCC1C(C(O)=O)C1(C)C.CC1(C)C2C1COC2=O.OC[C@H]1[C@H](C(O)=O)C1(C)C>C1(C)C=CC=CC=1.O>[CH3:15][C:7]1([CH3:14])[C@H:8]2[C@@H:6]1[CH2:12][O:11][C:9]2=[O:10]
Reactant: CCOC(=O)C1C(COC(C)=O)C1(C)C
Agent: CC1(C)C(CO)C1C(=O)O
Agent: CC1(C)C2COC(=O)C21
Agent: CC1(C)[C@@H](CO)[C@@H]1C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2C(=O)OC[C@@H]21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 13.5 kg of a solution containing 8.53 kg of ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate obtained in Production Example (39.8 mol, cis body/trans body ratio was 83.4/16.6, (1R)-cis body had an optical purity of 93.4% ee), 9.1 kg of water was added and the temperature thereof was raised up to 50° C., then, 24.2 kg of a 28% sodium hydroxide aqueous solution was dropped over a period of 4 hours, and the mixture was thermally kept at the same temperature for 2 hours. It was confirmed that ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate disappeared and was converted into 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid, then, to this solution was added 25.6 kg of toluene and the solution was mixed and separated, and the organic layer was removed. Further, to the aqueous layer was added 17.1 kg of toluene and the solution was mixed and separated, and the organic layer was removed likewise. To the resultant aqueous layer was added 21.8 kg of 35% hydrochloric acid at 20° C. and the mixture was thermally kept for 3 hours. It was confirmed that cis-3-hydroxymethyl-2,2-dimethyl-cyclopropanecarboxylic acid was converted into 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one, then, a 28% sodium hydroxide aqueous solution was dropped to adjust pH of the solution to 7. An extraction operation was repeated three times from this solution with 17.1 kg of toluene, and the resultant three toluene solutions were combined, to obtain 55.7 kg of a toluene solution containing 4.05 kg of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (32.1 mol, yield based on ethyl cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate: 96.7%). In this toluene solution, trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid was not detected.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1)[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:35]=[O:36])C.[NH4+].[Cl-]>C1COCC1>[C:23]([C@H:20]1[CH2:21][CH2:22][C@H:17]([O:16][C:7]2[C:8]([C:12]([F:14])([F:15])[F:13])=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([CH:35]=[O:36])[CH:11]=[CH:10]3)[CH2:18][CH2:19]1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2C(F)(F)F)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene (1 g, 2.3 mmol) in THF (30 mL) was added n-BuLi (2.8 mL, 2.5M in THF, 3.0 equiv) dropwise at −78° C. in 30 min, then DMF (840 mg, 11.5 mmol, 5.0 equiv) was added slowly at −78° C. The reaction mixture was stirred at −78° C. for 1.5 h. Then saturated NH4Cl solution was added to the mixture to quench the reaction. The mixture was extracted with EtOAc and purified by silica gel chromatography (petroleum ether:ethyl acetate 10:1) to give product 6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde as a yellow solid (608 mg, 70%) ESI-MS: 379.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 10.13 (s, 1H), 8.28 (d, 2H), 8.08 (d, 1H), 7.98-8.01 (dd, 1H), 7.41 (d, 1H), 4.39 (m, 1H), 2.21 (d, 2H), 1.90 (d, 2H), 1.49-1.58 (q, 2H), 1.10-1.17 (m, 3H), 0.86 (s, 9H).
Reaction SMILES: C(O[C:6]([N:8]1[CH:17]([C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]3=[O:32])=[CH:22][C:21]=2[F:33])[CH2:16]C2N=CC=CC=2C1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:18]([CH:17]1[NH:8][CH2:6][C:31]2[N:26]=[CH:27][CH:28]=[CH:29][C:30]=2[CH2:16]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1Cc2cccnc2CC1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)C1Cc2cccnc2CN1

Procedure:
A solution of 7-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (310 mg) in 8 ml dichloromethane and 1.53 ml TFA was stirred for 4 hrs at rt. The reaction mixture was poured onto 1M NaOH/ice and extracted twice with dichloromethane. The organic layers were dried over magnesium sulfate, evaporated and purified by chromatography (silica gel, AcOEt/methanol 9:1) to deliver the title compound as a light yellow solid (151 mg). MS: 365.5 (M+H)+
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:45])=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:45])=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Yield: 78 %

Procedure:
Prepared in 78% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J=7.7 Hz, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.42-7.35 (m, 1H), 7.32 (d, J=6.2 Hz, 1H), 7.29 (s, 1H), 6.99 (d, J=7.3 Hz, 1H), 5.89 (br. s., 1H), 4.62 (br. s., 1H), 3.92-3.81 (m, 1H), 3.61 (t, J=11.2 Hz, 1H), 3.46-3.41 (m, 2H), 3.12 (d, J=9.9 Hz, 1H), 2.64 (d, J=8.4 Hz, 1H), 2.40 (s, 3H), 1.93-1.50 (m, 10H), 1.19 (s, 3H), 1.16 (s, 9H), 1.07 (d, J=6.2 Hz, 3H); LCMS (ESI, M+): 661.3.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:16]#[N:17])[CH:7]=2.S(=O)(=O)(O)[OH:19]>>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:16]([NH2:17])=[O:19])[CH:7]=2
Reactant: Cn1c2c(c3cc(C#N)ccc31)C(=O)CCC2
Reactant: O=S(=O)(O)O
Product: Cn1c2c(c3cc(C(N)=O)ccc31)C(=O)CCC2

Procedure:
A solution of the product of Stage (i) cyanonitrile (2.7 g) in concentrated sulphuric acid (30 ml) was heated at 80° for 1 h. The mixture was poured onto ice (ca. 500 g) to precipitate a solid which was filtered, washed with water (3×50 ml) and dried in vacuo to leave a solid (3.1 g). This was extracted with boiling absolute ethanol (1.5 l), the extract was evaporated to ca 2 ml, diluted with a mixture of chloroform:methanol (1:1, ca 20 ml) and filtered to give the title compound (0.53 g) as a solid m.p. 295°-298°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:47]2[CH2:49][CH2:48]2)=[N:4][N:5]([CH2:45][CH3:46])[C:6]=1[N:7]1[CH2:44][CH2:43][C:10]2[N:11]=[C:12]([C:22]3[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]4[C:23]=3[C:24]([CH3:42])=[N:25][N:26]4S(C3C=CC(C)=CC=3)(=O)=O)[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[CH3:21])[C:9]=2[CH2:8]1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[C:3]([CH:47]2[CH2:48][CH2:49]2)=[N:4][N:5]([CH2:45][CH3:46])[C:6]=1[N:7]1[CH2:44][CH2:43][C:10]2[N:11]=[C:12]([C:22]3[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]4[C:23]=3[C:24]([CH3:42])=[N:25][NH:26]4)[N:13]=[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@H:16]3[CH3:21])[C:9]=2[CH2:8]1
Reactant: CCn1nc(C2CC2)c(Cl)c1N1CCc2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc(N3CCOC[C@H]3C)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCn1nc(C2CC2)c(Cl)c1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(N3CCOC[C@H]3C)c2C1
Temperature: 55 °C

Procedure:
To a solution of (R)-4-(6-(4-chloro-3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylmorpholine (0.081 g, 0.116 mmol) in MeOH (3 mL) was added K2CO3 (0.080 g, 0.578 mmol). The mixture was heated at 55° C. for 1 h 30 min. The methanol was removed under reduced pressure and the residue was taken up in water and the aqueous phase was neutralized to pH=6 (with 3 N HCl) and then extracted with EtOAc (3×). The combined organic phases were washed with brine, dried with sodium sulfate, filtered and concentrated under reduce pressure. Purification by FCC (0-4% MeOH/DCM) provided the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.58 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 4.33 (d, J=14.9 Hz, 1H), 4.18 (d, J=15.0 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 3.87-3.82 (m, 1H), 3.81-3.74 (m, 1H), 3.67 (dd, J=11.2, 2.9 Hz, 1H), 3.63-3.42 (m, 4H), 3.39-3.31 (m, 1H), 3.00-2.93 (m, 2H), 2.18 (s, 3H), 1.88 (s, 3H), 1.84-1.73 (m, 1H), 1.29-1.21 (m, 3H), 1.14 (d, J=6.6 Hz, 3H), 0.89-0.81 (m, 4H), 0.80-0.73 (m, 1H); MS (ESI+) m/z 547.2 (M+H)+.