Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[C:24]([NH:28][C:29]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(CO)CC[C@H]4[C@@H]3CC[C@@H]12
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(COC(=O)NC(C)(C)C)CC[C@H]4[C@@H]3CC[C@@H]12
Reaction time: 48 h

Procedure:
To a stirred solution of 17-(hydroxymethyl)-4-methyl-5α-4-azaandrostan-3-one (0.048 g, 0.15 mM) in dried benzene (5 mL) was added at room temperature t-butylisocyanate (0.03 mL, 0.23 mM) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.023 mL, 0.15 mM). After stirring for two days, the volatiles were removed in vacuo and the residue flash chromatographed on silica gel using ethyl acetate as eluant to give the title compound as a white solid. MS M+1 calculated for C25 H42N2O3, mw=418.55; observed m/e 419.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:25]=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C)C=O>O>[CH:26]([C:27]1[CH:35]=[CH:34][C:32]([O:33][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=2[CH3:8])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:25]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)c1cccc(-c2nc(CCl)c(C)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A mixture of methyl 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (3.0 g), potassium carbonate (1.42 g), vanillin (1.57 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (3.76 g, 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 168-169° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](F)=[CH:16][CH:15]=1>>[Br:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)=[CH:16][CH:15]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2ccc(Br)c3ccccc23)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][NH:27][CH2:26][C@@H:25]1[NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>ClCCl>[C:43]([N:27]1[CH2:28][C@@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])[CH:14]=3)[N:19]=2)[C@@H:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH2:26]1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: C=CC(=O)N[C@H]1CNC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CN(C(C)=O)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.37 g, 0.76 mmol) in dichloromethane (15 mL) at 0° C. was added DIEA (0.16 mL, 0.92 mmol) and acetyl chloride (0.054 mL, 0.76 mmol) and the reaction was stirred for 60 mins. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((3S,4R)-1-acetyl-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.207 g, 51%). MS (ES+) C25H25Cl2N5O4 requires: 529, found: 530.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])[S:2]1.[OH-].[Na+]>CO>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])[S:2]1
Reactant: COC(=O)CCNC(=O)CCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNC(=O)CCCCC1CCSS1
Yield: 54.3 %

Procedure:
The reaction was effected as described in Example 49, but using 213 mg of methyl 3-[5-(1,2-dithiolan-3-yl)pentanoylamino]propionate (prepared as described in Example 55), 4 ml of methanol and 1.80 ml of a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 0.11 g of the title compound as a pale yellow amorphous substance, melting at 74 to 76° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[CH:21]1([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C>[CH:21]1([CH2:27][C:28]([O:1][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4](=[O:18])[CH:3]=2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 35 minutes. Then, cyclohexylacetyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 80 minutes. Thereafter, water was added to the reaction mixture, and the precipitate was separated by filtration and dried to give 4-cyclohexylacetoxy-1-phenyl-1,8-naphthyridin-2(1H)-one as a form of crystal (1.33 g, yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([CH2:31][CH2:32][C:33]([N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[O:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)CCc2ccc3c(c2)sc2ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]propanoic acid (25 mg, 0.05 mmol, 1 equiv), 4-methyl piperazine (6 mg, 0.06 mmol, 1.2 equiv), 1-[3-(dimethylaminopropyl)]-3-ethyl carbodiimide (14.1 mg, 0.07 mmol, 1.5 equiv), 4-methyl morpholine (10 mg, 0.1 mmol, 2 equiv) and 1-hydroxybenzotriazole (14 mg, 0.1 mmol, 2 equiv) were mixed in DMF and stirred at rt for 16 h. Water and EtOAc were added and extraction was preformed 3 times. Organic layers was concentrated and purified by preparative TLC using 5% MeOH/DCM to yield a solid product (18.5 mg, 64%). 1H-NMR (DMSO-d6) δ 8.94 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 7.96 (d, 1H), 7.74 (d, 1H), 7.52 (dd, 1H), 7.45 (m, 2H), 7.30 (m, 2H), 7.23 (d, 1H), 7.16 (m, 1H), 5.26 (s, 2H), 3.41 (m, 4H), 2.99 (t, 2H), 2.72 (t, 2H), 2.20 (m, 4H), 2.13 (s, 3H); LCMS RT=2.87 min, [M+H]+=590.2
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[N:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]([Br:22])=[N:20][C:19]([Br:23])=[N:18]2)=[C:12]([CH3:24])[C:9]=1[C:10]#[N:11].[CH:25]1([NH:28][C:29]2[C:38]([CH3:39])=[CH:37][C:36]([OH:40])=[CH:35][C:30]=2[C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1>CN(C=O)C>[C:10]([C:9]1[C:8]([O:40][C:36]2[CH:37]=[C:38]([CH3:39])[C:29]([NH:28][CH:25]3[CH2:27][CH2:26]3)=[C:30]([CH:35]=2)[C:31]([O:33][CH3:34])=[O:32])=[N:15][CH:14]=[C:13]([CH2:16][N:17]2[C:21]([Br:22])=[N:20][C:19]([Br:23])=[N:18]2)[C:12]=1[CH3:24])#[N:11]
Reactant: Cc1c(Cn2nc(Br)nc2Br)cnc(Cl)c1C#N
Reactant: COC(=O)c1cc(O)cc(C)c1NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ncc(Cn3nc(Br)nc3Br)c(C)c2C#N)cc(C)c1NC1CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Cs2CO3 (14.9 g, 45.8 mmol) and DMF (25 mL) are added into a 250 mL flask, and the reaction mixture is heated to 80° C. 2-chloro-5-((3,5-dibromo-1H-1,2,4-triazol-1-yl)methyl)-4-methylnicotinonitrile (7.2 g, 18.3 mmol) and hydrochloride salt of methyl 2-(cyclopropylamino)-5-hydroxy-3-methylbenzoate (4.2 g, 18.3 mmol) is dissolved by DMF (25 mL) in a 100 mL flask, and the mixture is added into the 250 ml flask over 30 min. The resulting mixture is stirred at 80° C. for 30 min. A sample of the mixture is taken for HPLC analysis. The reaction mixture is kept stifling until the conversion to product is at least 99%. Then, the reaction mixture is cooled to 20° C., and the reaction is quenched with EtOAc (50 mL) and water (50 mL). The bottom aqueous layer is then removed, and the organic layer is washed with two times of 10% NaCl (40 mL each). The solvent of the organic layer is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅙ of original volume. Then the resulting solvent is passed through a pad of silica gel (15 g) by 4:1 hexanes/EtOAc (100 mL). The resulting solvent is then distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. Then MeOH (70 mL) is added into the solvent, and the resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. Another 70 ml of MeOH is added into the solvent, and the resulting solvent is distilled under vacuum with internal temperature of the solvent as between 30˜45° C. to ⅛ of original volume. An additional 70 ml of MeOH is added into the solvent, and the resulting solvent is heated to 60° C., then is cooled down to 20° C. in 2 h and stirred at 20° C. for 2 h. The resulting mixture is filtered, and the filter cake is washed with MeOH (15 mL). The filter cake is then dried under vacuum at 20° C. to afford 8 g product with more than 97% purity.
Reaction SMILES: [O-]CC.[Na+].C(OCC)(=O)C.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[N:22]([CH2:35][CH2:36][CH3:37])[C:23](=[O:34])[N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:25]=2)=[CH:14][CH:13]=1.[C:38]([O:43][CH:44](CC)[CH2:45]CC)(=[O:42])[CH:39]([CH3:41])[CH3:40].Cl>C(O)C.O.C(OC(CC)CCC)(=O)C(C)C>[CH2:44]([O:43][C:38](=[O:42])[C:39]([CH3:41])([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[N:22]([CH2:35][CH2:36][CH3:37])[C:23](=[O:34])[N:24]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[N:25]=2)=[CH:14][CH:13]=1)[CH3:40])[CH3:45]
Reactant: CCCn1c(CCCc2ccc(O)cc2)nn(Cc2ccc(C)cc2)c1=O
Reactant: CCCC(CC)OC(=O)C(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCn1c(CCCc2ccc(OC(C)(C)C(=O)OCC)cc2)nn(Cc2ccc(C)cc2)c1=O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a mixture of sodium ethoxide (1.22 mL, 3.28 mmol) and ethyl acetate (322 μL, 3.28 mmol) was added 5-[3-(4-hydroxyphenyl)-propyl]-2-(4-methylbenzyl)-4-propyl-2,4-dihydro-[1,2,4]triazol-3-one (1.2 g, 3.28 mmol) in ethanol (10 mL) and the resulting mixture stirred at reflux for 1 hour. Then ethyl-2-butyl isobutyrate (1.08 mL, 7.38 mmol) was added and the reaction continued at reflux for 1 hour. Then sodium ethoxide (1.22 mL, 3.28 mmol) was added dropwise over 5 min and the reaction continued at reflux for 4.5 hour. Additional sodium ethoxide (520 μL, 1.4 mmol) and ethyl-2-butyl isobutyrate (205 μL, 1.4 mmol) were added and reaction continued at reflux for 4 hour. Additional sodium ethoxide (336 μL, 0.903 mmol) and ethyl-2-butyl isobutyrate (132 μL, 0.903 mmol) were added and the reaction continued at reflux for 3 hours. Finally, additional sodium ethoxide (200 μL, 0.54 mmol) and ethyl-2-butyl isobutyrate (100 μL, 0.133 mmol) were added and the reaction continued at reflux for 1.5 hours. The mixture was allowed to cool to room temperature and is then quenched into a solution of conc. HCl (1.5 g, 41 mmol) in water (50 mL). The resulting solution was then concentrated in vacuo, taken up in ethyl acetate (100 mL) and the aqueous layer was discarded. The organic layer was washed with saturated aq. NaHCO3 (2×50 mL) followed by saturated aq. NaCl (2×25 mL). The organic layer was dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (1:1 ethyl acetate:hexanes) to afford the title compound as a yellow oil (990 mg, 2.06 mmol, 63%):
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:14]1[CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH:14]1[CH2:15][CH2:16][CH2:17]1)[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C1CCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCO)C1CCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
To a solution of 3-tert-butoxycarbonylamino-3-cyclobutyl-propionic acid (0.300 g, 1.23 mmol) in THF (12 mL) was added BH3—SMe2 (1.70 mL, 3.33 mmol; 2.0 M solution in THF) at 0° C. After stirring at rt for 10 h, the reaction mixture was quenched with satd. NaHCO3, extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford (1-cyclobutyl-3-hydroxy-propyl)-carbamic acid tert-butyl ester (0.100 g); LC-MS [M+H]+ 230.0. The product is sufficiently pure for the next step and used for the next step without further purification.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCCCCCCCCCC1.[O:26]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:27]12.O=O.[B]>>[CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1(=[O:26])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: C1CCCCCCCCCCC1
Agent: O=C1CCCCCCCCCCC1
Agent: O=O
Product: OC1CCCCCCCCCCC1

Procedure:
The starting cyclododecanone material usable for the process of the present invention can be prepared by oxidizing cyclododecane with a molecular oxygen-containing gas or by isomerizing epoxycyclododecane. In the oxidation method, cyclododecane is oxidized with oxygen gas or a molecular oxygen-containing gas in the presence of a boron compound to provide a reaction product mixture comprising cyclododecanol and cyclododecanone, the reaction product mixture is hydrolysed, the boron compound is removed from the hydrolysis product mixture, non-reacted cyclododecane is separated and recovered from the hydrolysis product mixture by distillation, and a mixture of cyclododecanol with cyclododecanone is collected from the residual fraction. The mixture is subjected to a dehydrogenation procedure to convert cyclododecanol to cyclododecanone. In this dehydrogenation procedure, a portion of the resultant cyclododecanone is occasionally further dehydrogenated to produce cyclododecenone.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][C:10]#[N:11].[OH-].[Na+]>C1COCC1>[NH2:11][CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:7]
Reactant: N#CCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCC(O)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred suspension of LAH (20 g, 517 mmol) in dry THF (500 mL) was added a solution of 3-oxo-3-phenylpropanenitrile (30 g, 207 mmol) in dry THF (300 mL) drop-wise at 0° C. under nitrogen atmosphere. The mixture was warmed to 25° C. and then heated at 70° C. for 2 hours. After cooling to 0° C., a saturated solution of sodium hydroxide was added drop-wise and extracted with dichloromethane (200 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (methanol:dichloromethane, 1:10) to afford crude 3-amino-1-phenyl-propan-1-ol. (Yield 30 g). LC-MS: [M+H]+ 152.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:41])[N:12]2[C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=3[F:32])[C:18]([O:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:17][C:16]=2[Cl:40])=[C:8]([O:42][CH3:43])[N:7]=1)(=O)C.O.[OH-].[Li+].CO.Cl>O1CCCC1.O>[C:35]([CH2:34][O:33][C:18]1[C:19]([O:21][CH2:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=2[F:32])=[CH:20][C:15]([N:12]2[C:11](=[O:41])[NH:10][C:9]3[C:13]2=[N:14][C:6]([CH2:5][OH:4])=[N:7][C:8]=3[O:42][CH3:43])=[C:16]([Cl:40])[CH:17]=1)([OH:37])=[O:36]
Reactant: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(COC(C)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)c(Cl)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A mixture of 2-acetyloxymethyl-9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (60 mg) and lithium hydroxide monohydrate (81 mg) in tetrahydrofuran (4 mL)-methanol (2 mL)-water (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (42 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[N:6]([CH3:14])[C:5]2(O)[C:15]([NH:17][C:18]([NH2:20])=S)=[O:16].[H-].[Na+].C(Br)C.CN(C)C=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3([C:15](=[O:16])[NH:17][C:18](=[O:30])[NH:20]3)[N:6]([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[CH:10][C:11]=1[Cl:12]
Reactant: CN(C)C=O
Reactant: CN1C(=O)Nc2cc(Cl)c(Cl)cc2C1(O)C(=O)NC(N)=S
Agent: [H-]
Agent: [Na+]
Solvent: CCBr
Product: CN1C(=O)Nc2cc(Cl)c(Cl)cc2C12NC(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,7-Dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (2.8 g) is dissolved in dimethylformamide (30 ml), and thereto is added sodium hydride (60% oily suspension) (0.32 g), and the mixture is stirred at room temperature for 30 minutes. To the mixture is added ethyl bromide (2 ml), and the mixture is further stirred for 30 minutes, and then the solvent is distilled off under reduced pressure. To the residue [i.e. 6,7-dichloro-3-methyl-4-hydroxy-4-(2-methylisothioureido)-carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline] is added 10% hydrochloric acid (30 ml), and the mixture is stirred at 70° C. for 4 hours. After cooling, the precipitates are taken by filtration, washed with 10% aqueous sodium hydrogen carbonate solution and then recrystallized from dimethylformamide-water to give 6,7-dichloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]([NH2:14])=O.O=P(Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]#[N:14]
Reactant: COc1ccc2[nH]cc(C(N)=O)c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]cc(C#N)c2c1
Yield: 59.8 %

Procedure:
5-Methoxy-1H-indole-3-carboxamide (6.1 g) was treated with refluxing POCl3 (65 ml) for ten minutes. Excess POCl3 was removed under high vacuum (0.1 mmHg) and the residue quenched with water/0.88 NH4OH 1:1 (100 ml). The resulting solution was extracted with CHCl3 (4×100 ml), treated with charcoal (10 g), dried (MgSO4), filtered and the solvent removed to afford a brown solid. Recrystallisation from hexane afforded the title compound as pale brown needles (3.3 g), m.p. 147° C.; δH (360 MHz, CDCl3) 3.86 (3H, s, OCH3), 6.90 (1H, dd, J=7.5, 1.0 Hz, H-6), 7.13 (1H, d, J=1.0 Hz, H-4), 7.36 (1H, d, J=7.5 Hz, H-7), 7.67 (1H, s, H-2).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28](Cl)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[C:44]([Cl:46])[CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:39][C:40]1[CH:41]=[C:42]([C:28]2[C:27]3[C:32](=[CH:33][C:24]([CH2:23][N:21]4[CH:22]=[C:18]([C@:11]([OH:10])([C:14]([F:16])([F:17])[F:15])[CH2:12][CH3:13])[N:19]=[N:20]4)=[CH:25][CH:26]=3)[N:31]=[C:30]([C:34]#[N:35])[CH:29]=2)[CH:43]=[C:44]([Cl:46])[CH:45]=1
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C#N)nc3c2)nn1)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-1-{1-[(4-chloro-2-cyanoquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate (150 mg, 0.28 mmol) in DME (3 mL) was added tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), 3,5-dichlorophenylboronic acid (80 mg, 0.42 mmol) and aq. 2M Na2CO3 (0.42 mL, 0.84 mmol). After 1.5 h at 100° C., the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. To this crude product was added THF (4 mL) and LiOH IM (1.4 mL, 1.4 mmol). After 2 h at rt, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with EtOAc/hexanes, 3:7) gave the title compound. MS (+ESI): 506 (M+H)+.