Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][C:15](O)=[O:16])=[CH:4][CH:3]=1.Cl.[CH3:25][NH:26][O:27][CH3:28].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>O.CN(C)C=O.C(N(CC)CC)C>[CH3:28][O:27][N:26]([CH3:25])[C:15](=[O:16])[CH2:14][CH2:13][C:12]1[O:11][C:10]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH3:23])=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
Triethylamine(505 mg) was added dropwise to a N,N-dimethylformamide solution of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid(1.50 g) and N,O-dimethylhydroxyamine hydrochloride(490 mg) at 0° C. 1-Hydroxybenzotriazole hydrate(HOBt, 760 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(WSC, 950 mg) were added thereto. The reaction mixture was stirred for 20 hours at room temperature. Water was poured into the reaction mixture. Saturated sodium bicarbonate solution was added to make the mixture alkaline. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated, and the precipitated crystals were collected by filtration to give N-methoxy-N-methyl-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide(1.54 g, 91%). This was recrystallized from acetone-isopropyl ether to give colorless prisms. mp 116-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]CS([O-])(=O)=O)=[CH:5][CH:4]=1.Br.Br.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:18]2[CH2:19][CH2:20][CH:21]([NH:24][C:25]3[S:26][C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[CH2:22][CH2:23]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: c1ccc2sc(NC3CCNCC3)nc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(Nc3nc4ccccc4s3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 2.3 parts of [2-(4-methoxyphenyl)ethyl]methanesulfonate, 4 parts of N-(4-piperidinyl)-2-benzothiazolamine dihydrobromide, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured onto water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.5 parts (41%) of N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-2-benzothiazolamine; mp. 142.5° C. (178).
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[C:21][Si](C)(C)C)[CH:15]=2)=[C:12]2[C:7]([C:8]([C:26]([F:29])([F:28])[F:27])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:20]([C:16]1[CH:15]=[C:14]([C:13]2[N:5]([CH2:4][C:3]3[C:30]([F:35])=[CH:31][C:32]([F:34])=[CH:33][C:2]=3[F:1])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[C:8]3[C:26]([F:29])([F:27])[F:28])[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Temperature: 50 °C
Yield: 91.9 %

Procedure:
A mixture of 2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-3-{3-[(trimethylsilyl)-ethynyl]phenyl}-2H-indazole (1.78 g, 3.54 mmol) and potassium carbonate (0.49 g, 3.54 mmol) in 50 mL of methanol was heated at 50° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo to give 1.4 g of a white solid, which was purified by flash chromatography (silica gel 60, hexane-ethyl acetate, 4:1) to give 1.1 g of the title compound.
Reaction SMILES: [H-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].S(OC)(O[CH3:30])(=O)=O>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)([CH2:16][O:17][CH3:30])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(CC2(CO)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1(Cc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium hydride (0.40 g, dry weight, 10 mmol; obtained from washing 0.97 g of 35% potassium hydride dispersion in mineral oil with hexanes and drying under a stream of argon) in anhydrous THF (45 mL), N-tert-butoxycarbonyl-4-(3-methylbenzyl)-4-hydroxymethylpiperidine (1.89 g, 5.9 mmol) in THF (15 mL) was added. The resultant mixture was stirred at room temp. for 1 h, and treated with dimethyl sulfate (1.13 mL, 11.9 mmol). The reacting mixture was stirred at room temp. overnight. The product mixture was cooled to 0° C., quenched with water, and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2].[CH3:24][C:25]1([CH3:49])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]2[CH:30]=[C:29](/[C:37](/[CH3:48])=[CH:38]/[C:39]3[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=3)[CH:28]=[CH:27][C:26]1=2>N1C=CC=CC=1.CCOCC>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[O:8][CH:6]1[O:7][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39](/[CH:38]=[C:37](/[C:29]2[CH:28]=[CH:27][C:26]3[C:25]([CH3:49])([CH3:24])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]=3[CH:30]=2)\[CH3:48])=[CH:40][CH:41]=1)(=[O:3])[CH3:2]
Reactant: C/C(=C\c1ccc(C(=O)Cl)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)[C@H]1OC(OC(=O)c2ccc(/C=C(\C)c3ccc4c(c3)C(C)(C)CCC4(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.4 g of methyl 2,3,4-tri-O-acetyl-α-D-glucopyranuronate in 40 ml of pyridine was reacted at 0° C. with a solution of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl chloride in 70 ml of ether. The mixture was stirred at room temperature overnight, evaporated to dryness and the residue was chromatographed on silica gel with hexane/ethyl acetate. There was obtained methyl 2,3,4-tri-O-acetyl-1-O-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl]-D-glucopyranuronate as a mixture of the β- and α-anomers (ca 4:1). Melting point 149°-150° C. (from ethanol); [α]D25 =3° (c=1 in chloroform).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[NH:20][N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH3:5].[H-].[Na+].I[CH3:40]>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[N:20]([CH3:40])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[CH:10]=1)=[O:8])[CH3:5]
Reactant: CI
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)cc(F)c34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
A 50 mL round-bottomed flask was charged with 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (120 mg, 0.225 mmol) and DMF (0.45 ml) to give a light yellow solution. The reaction mixture was placed under argon atmosphere and cooled in a 0° C. bath. NaH (60% in mineral oil, 23 mg, 0.575 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 10 min then returned to the cooling bath and iodomethane (21 μl, 0.34 mmol) was added. The reaction was stirred at 0° C. for 10 min then the bath was removed and stirring continued at room temperature for an additional 18 h. The reaction was quenched with water and the precipitate collected by filtration. The crude material was purified by chromoatography over SiO2 with EtOAc/heptane (gradient: 0-100% EtOAc) to afford 41 mg (33%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=547.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[SH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][S:16][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:19])[CH3:22]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CSc1c(C(=O)OCC)[nH]c2ccccc12
Yield: 21 %

Procedure:
To a solution of ethyl 3-bromoindole-2-carboxylate (1.34 g) and ethyl 2-mercaptoacetate (0.96 ml) in acetone (15 ml) was added potassium carbonate (1.38 g) and the resulting mixture was heated at reflux under argon for 18 hours. The cooled mixture was poured into water and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated to a gum which was purified by column chromatography using iso-hexane:ethyl acetate (1:4) to give the desired product (331 mg, 21%) NMR d (CDCl3) 1.05 (t, 3H), 1.45 (t, 3H), 3.6 (s, 2H), 4.0 (q, 2H), 4.5 (q, 2H), 7.2-7.4 (m, 3H), 7.9 (d, 1H), 9.2 (brs, 1H); M/z (+) 308.3 (MH30).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:3]=1[O:4][C:5](=[O:23])[C:6]1[C:15]2=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([CH3:22])=[CH:9][C:10]([CH3:21])([CH3:20])[NH:11]2.CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:26][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:3]=1[O:4][C:5](=[O:23])[C:6]1[C:15]2=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([CH3:22])=[CH:9][C:10]([CH3:20])([CH3:21])[NH:11]2
Reactant: O=C([O-])[O-]
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1c(O)cccc13
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1oc(=O)c1c3c(ccc12)NC(C)(C)C=C3C
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A mixture of 7-Hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-9, 430 mg, 1.40 mmol), methyl iodide (87.2 μL, 1.40 mmol) and potassium carbonate (387 mg, 2.80 mmol) was suspended in anhydrous N,N-dimethylformamide (7 mL) and stirred at 50° C. for 3 hours. After cooling down, the reaction mixture was diluted with ethyl acetate (150 mL). The whole was washed with water (150 mL) and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (384 mg) as a yellow solid. (Yield 85%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[C:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:23].CCOC(C)=O.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[CH:27][CH:26]=1)#[N:23]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#CCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (60 mg, 0.162 mmol), [4-(cyanomethyl)phenyl]boronic acid (52.0 mg, 0.323 mmol) and K2003 (67.0 mg, 0.485 mmol) in 1,4-dioxane (0.18 mL) and water (0.08 mL) was degassed in a Biotage microwave vial for 10 min. PdCl2(dppf) (11.83 mg, 0.016 mmol) was added, the vial sealed, and the reaction heated at 100° C. for 5 min (microwave reaction). EtOAc (3 mL) and water (1 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4×2 mL). The combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), and concentrated under a stream of nitrogen at 50° C. Recovered 27 mg (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:19][CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[C:10]=2[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (0.110 g, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 μmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (0.089 g, 49%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.52-1.75 (2H, m), 2.05-2.16 (2H, m), 2.92-3.10 (2H, m), 4.08-4.25 (2H, m), 4.35-4.42 (1H, m), 6.87 (1H, d, J=8.4 Hz), 7.63 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.8 Hz), 8.62 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26]CC)=[O:25])[CH:18]=[N:17]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[N:17]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(C(=O)O)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoxaline-2-carboxylate (500 mg, 1.3 mmol) in EtOH/THF (5 mL) was added NaOH (5 ml, 2 mmol) followed by stirring for 2 hrs at r.t. After extraction by EA, the combined organic layers were concentrated in vacuo to yield 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoxaline-2-carboxylic acid as a red solid (260 mg, yield: 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][CH3:14])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>C1COCC1>[CH2:13]([CH:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:15]([O:17][CH2:24][C:21]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)=[O:16])[CH2:10]1)[CH3:14]
Reactant: CCC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: CCC1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A mixture of (2S)-1-(tert-butoxycarbonyl)-4-ethylpyrrolidine-2-carboxylic acid (45.5 g, 187 mmol), TEA (37.8 g, 374 mmol) in THF (1 L) was added dropwise BnBr (38.5 g, 225 mmol) at 0° C. The mixture was stirred at room temperature overnight. TLC showed the reaction was completed. The mixture was concentrated to remove solvent. The residue was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to give (2S)-2-benzyl 1-tert-butyl 4-ethylpyrrolidine-1,2-dicarboxylate (46 g, 74%) as colorless oil. (2S)-2-benzyl 1-tert-butyl 4-ethylpyrrolidine-1,2-dicarboxylate was separated by preparative SFC via a Chiralcel OD 250*50 mm i.d. 10 μm column (Mobile phase: A for n-hexane and B for ethanol (0.05% IPAm), Gradient: A: B=97:3, Flow rate: 100 ml/min, Wavelength: 210 and 220 nm, Injection amount: 0.4 g per injection) to provide (2S,4S)-2-benzyl 1-tert-butyl 4-ethylpyrrolidine-1,2-dicarboxylate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[OH:14])(=O)=O)=CC=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:27]([CH2:12][C@H:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[OH:14])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc([C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([C@H](O)CN=[N+]=[N-])cc(OC)c1OC

Procedure:
A solution/slurry of Example 23C (450 mg; 1.2 mmol) and sodium azide (153 mg; 2.4 mmol) in DMF (5 mL) was heated at 80-90° C. for 2 hours, treated with brine, and extracted with ethyl acetate. The extract was washed with brine (2×), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 30% ethyl acetate/hexane) to provide 223 mg (75%).the desired product as a nearly colorless oil.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]1([C:18]2[C:27]([CH:28]([OH:39])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[C:26]([CH:40]([CH3:42])[CH3:41])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:45])[CH2:21][C:22]([CH3:44])([CH3:43])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.CO>O1CCCC1>[C:12]1([C:18]2[C:27]([C@H:28]([OH:39])[C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[C:26]([CH:40]([CH3:41])[CH3:42])[CH:25]=[C:24]3[C:19]=2[C@@H:20]([OH:45])[CH2:21][C:22]([CH3:43])([CH3:44])[O:23]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: CC(C)c1cc2c(c(C3=CCCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
230 μl (1.27 mmol) of borane/N,N-diethylaniline complex are added very slowly to a solution of 7.10 mg (50 μmol) of (1R,2S)-1-aminoindan-2-ol in 7.5 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 min. A solution of 150 mg (320 μmol) of 5-cyclohex-1-en-1-yl-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 35A) in 7.5 ml of tetrahydrofuran are then added very slowly dropwise over a period of 30 min. The mixture is stirred overnight, methanol is then added and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→1:1) and subsequent preparative HPLC (method 1) gives the diastereomerically pure target compounds, which for their part are present as a mixture of two rotamers.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](I)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](B(O)O)=[CH2:27])=[CH:22][CH:21]=1.N12CCCN=C1CCCCC2.O>CN1CCCC1=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[CH2:27])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Reactant: C=C(B(O)O)c1ccc(F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(c1ccc(F)cc1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 110 °C

Procedure:
6-(3,5-Dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.28 mmol), 1-(4-Fluorophenyl)vinylboronic acid, pinacol ester (209.59 mg, 0.84 mmol), PEPPSI″-IPr catalyst (19.19 mg, 0.03 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene solution (0.25 ml, 1.69 mmol) were mixed in 1-Methyl-2-pyrrolidinone (6 ml) and Water (3 ml) in sealed in a microwave vial and heated to 110° C. for 30 minutes in a microwave reactor. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with water then brine and dried over sodium sulfate. Purification on silica gel (Hexane/EtOAc) followed by preparative HPLC afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)vinyl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]3[S:19][C:20]([CH2:22][OH:23])=[CH:21][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:26][O:23][CH2:22][C:20]2[S:19][C:16]3[C:17](=[O:18])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:24])[CH3:1])=[CH:7][CH:8]=4)[CH:13]=[N:14][C:15]=3[CH:21]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CN(C)CCOc1ccc(-n2cnc3cc(CO)sc3c2=O)cc1
Reactant: BrCC1CCC1
Product: CN(C)CCOc1ccc(-n2cnc3cc(COCC4CCC4)sc3c2=O)cc1

Procedure:
3-[4-(2-Dimethylaminoethoxy)phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one was reacted with (bromomethyl)cyclobutane by method V. The product with the molecular weight of 413.54 (C22H27N3O3S) was obtained in this way; MS (ESI): 414 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[S:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6]1.[CH2:13](O)[CH3:14]>CN(C)C1C=CN=CC=1>[S:5]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6]1
Reactant: O=C(O)c1ccsc1
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccsc1
Reaction time: 48 h
Yield: 91 %

Procedure:
13 ml (200 mmol) of thionyl chloride are added dropwise, at 0° C., to a solution of 9 g (70 mmol) of 3-thiophenecarboxylic acid and 86 mg (0.7 mmol) of 4-dimethylaminopyridine in 100 ml of ethanol. The reaction medium is stirred from 0° C. to room temperature over 48 hours and then evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 1/1 heptane/dichloromethane mixture. 10 g (91%) of ethyl thiophene-3-carboxylate are obtained.