Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[NH:58][CH:57]=2)[CH2:52][CH2:51]1>CN(C)C=O>[CH3:17][O:16][C:7]1[CH:6]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:47][CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][CH:53]([C:56]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[NH:58][CH:57]=3)[CH2:54][CH2:55]2)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)O)cc1OC
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoic acid (1.35 g) and triethylamine (1.17 ml) in dry N,N-dimethylformamide (8 ml) was added slowly diphenyl phosphinic chloride (0.97 g) at -10° to -15° C. under an inert atmosphere. After being stirred for 1 hour, a solution of 1-(2-aminoethyl)-4-(3-indolyl)piperidine (0.97 g) in dry N,N-dimethylformamide (8 ml) was added slowly to the reaction mixture at the same temperature. After being stirred for 40 minutes at the same temperature, the reaction mixture was poured into ice-water (160 ml) and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated to give syrup of 1-[2-[5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoylamino]ethyl]-4-(3-indolyl)piperidine (1.97 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[N:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([NH:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:19])([F:29])[F:30])=[O:18])[CH2:14][CH2:15]2)[N:3]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)O)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a suspension of 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (885 mg, 3.25 mmol, 1.00 equiv) in DMF (32 ml) at room temperature, {[2-(trifluoromethyl)phenyl]methyl}amine (456 μL, 3.25 mmol, 1.00 equiv), EDCI (748 mg, 3.90 mmol, 1.20 equiv), HOBT (527 mg, 3.90 mmol, 1.00 equiv), and diisopropylethylamine (DIEA, 2.80 ml, 16.3 mmol, 5.00 equiv) were added. Stirring was continued overnight at room temperature. The reaction mixture was partitioned between 1:1 water and ethyl acetate (200 ml). The product was extracted three times with ethyl acetate (50 ml). The ethyl acetate extracts were combined and washed successively with saturated ammonium chloride (100 ml), water (100 ml), and saturated sodium chloride (100 ml). The ethyl acetate solution was dried with Na2SO4, filtered, and concentrated under reduced pressure to yield 1.23 g (88%) of the title compound. MS ES+): m/e 428.7 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([Br:15])[CH3:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C(C)Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-hydroxy-ethyl)-benzoic acid methyl ester (Step B, 2.12 g, 11.7 mmol) in CH2Cl2 (25 mL) at 0° C. were added carbon tetra bromide (5.07 g, 15.3 mmol) and triphenylphosphine (3.71 g, 14.04 mmol). The reaction mixture was stirred overnight at room temperature, after completion of the reaction, was poured into H2O (50 mL). The aqueous solution was extracted with CH2Cl2 (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography in hexanes/ethyl acetate (5%) to afford 4-(1-bromo-ethyl)-benzoic acid methyl ester as a colorless liquid. (2.45 g, 85%): 1H NMR (300 MHz, CDCl3): δ 8.0 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 5.11 (q, J=6.9 Hz, 1H), 3.91 (s, 3H), 1.83 (d, J=6.9 Hz, 3H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH:28]([CH3:29])[CH2:27][NH:26][CH2:25][CH:24]1[CH3:30])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH:28]([CH3:29])[CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH:24]1[CH3:30])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC1CNCC(C)N1C(=O)OC(C)(C)C
Product: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C

Procedure:
Intermediate 1 was coupled with 2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccc(-c2cccs2)n1
Product: CN(C(=O)On1ccc(-c2cccs2)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-thienyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (66%, oil).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]4OCC[O:58]4)[CH:52]=3)[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:67])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]=[O:58])[CH:52]=3)[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4cccc(C5OCCO5)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4cccc(C=O)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Yield: 31.5 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(3'"-dioxolanylphenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (20 mg in 1 ml methylene chloride) was added 1 ml of a 2.2% solution of p-toluensulfonic acid in methanol and the mixture stirred at room temperature. After 20 minutes the reaction was quenched by the addition of 2 ml saturated sodium bicarbonate, extracted with methylene chloride and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by preparative tlc on silica gel (2:1, hexane/acetone) to give the title compound (6 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[C:10]([Cl:22])[CH:9]=2)=[O:4].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[Cl:22])[N:7]=[C:6]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cl)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1
Reactant: C1CCNCC1
Product: O=C(O)c1c(N2CCCCC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,7-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester and piperidine. Brown solid. MS (ESI): 401.1 (M+H)+.
Reaction SMILES: [S-]C#N.[NH4+].Br.C(N1CCC(=O)C(Br)C1)(=[O:8])C.C([N:20]1[CH2:25][CH2:24][C:23](=O)[CH:22]([S:27][C:28]#[N:29])[CH2:21]1)(=O)C.Cl>O>[NH:29]1[C:23]2[CH2:24][CH2:25][NH:20][CH2:21][C:22]=2[S:27][C:28]1=[O:8]
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Reactant: CC(=O)N1CCC(=O)C(SC#N)C1
Agent: Br
Agent: Cl
Agent: N#C[S-]
Solvent: O
Product: O=c1[nH]c2c(s1)CNCC2
Yield: 6 %

Procedure:
Ammonium thiocyanate (5.54 g, 72.8 mmol) was mixed with water (450 ml) and heated to 80°. A solution of N-acetyl-3-bromo-4-piperidone hydrobromide (20.0 g, 66.2 mmol) in water (200 ml) was added dropwise over 3 hours. The reaction was then allowed to stir at 80° for sixteen hours. The reaction solution (containing the crude N-acetyl-3-thiocyanato-4-piperidone) was treated with concentrated hydrochloric acid (6 ml of a 12M solution, 93 mmol) and heated to reflux for 2 hours. The reaction mixture was then freeze-dried, and the residue dissolved in methanol and filtered. The precipitate was purified by column chromatography (eluant: 89:10:1 chloroform:methanol: concentrated ammonium hydroxide) to provide the title product as a white solid, m.p. 208° (decomp.) (0.60 g, 3.8 mmol, 6% yield).
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][C@H:10]1[CH3:19])C1C=CC=CC=1>CO.[Pd]>[CH3:19][C@H:10]1[C@H:9]([NH2:8])[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:11]1
Reactant: C[C@@H]1CC2(CC[C@H]1NCc1ccccc1)OCCO2
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CC2(CC[C@H]1N)OCCO2
Reaction time: 8 h

Procedure:
A mixture of (7R,8R)—N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (640 mg, 2.4 mmol) and Pd/C (10%, 52 mg) in MeOH (50 mL) was left to stir under H2 (1 atm) overnight. The mixture was filtered through celite, and concentrated to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 3.91 (m, 4H); 1.15-2.12 (series of m, 7H); 0.96 (d, 3H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:32]=[CH:31][C:7]([C:8]([NH:10][CH2:11][C@@H:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][N:13]2[S:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)(=[O:20])=[O:19])=[O:9])=[CH:6][CH:5]=1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[SH:17][C@H:15]1[CH2:14][N:13]([S:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)(=[O:19])=[O:20])[C@H:12]([CH2:11][NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:33])=[O:2])=[CH:32][CH:31]=2)[CH2:16]1
Reactant: COC(=O)c1ccc(C(=O)NC[C@@H]2C[C@@H](S)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)NC[C@@H]2C[C@@H](S)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A degassed solution of 102 mg (0.21 mmol) (2S,4R)-N-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-terephthalamic acid methyl ester in 12.6 ml THF was treated with 12.6 ml 0.1 M aqueous LiOH (1.26 mmol, 6 eq) at 0° C. and was stirred at room temperature for 1.5 h. 1 M KHSO4 solution was added (pH 2), the layers were separated and the inorganic one was extracted with EtOAc. The combined organic ones were washed with water and brine, dried over Na2SO4 and evaporated, yielding (2S,4R)-N-[4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-ylmethyl]-terephthalamic acid as white foam, MS: 471 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:28])=[C:15]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(Cl)cc(C(F)(F)F)c3)sc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2cc(Cl)cc(C(F)(F)F)c2)nc1Cn1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of the compound (230 mg, 0.54 mmol) obtained in Example 83a in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (1.1 mL, 2.2 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (150 mg, 70%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[NH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: C[C@H](N)CO
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](CO)Nc1cc(Cl)nc(Cl)n1
Reaction time: 12 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine (4.70 g, 25.6 mmol) and triethylamine (7.78 g, 77.0 mmol) in acetonitrile (150 mL) was added a solution of (S)-2-aminopropan-1-ol (2.31 g, 30.7 mmol) in acetonitrile (150 mL) at 0° C. The reaction mixture was allowed to room temperature and stirred for 12 h, then filtered and concentrated. Purification via column chromatography (elutriant: petroleum ether/ethyl acetate=4/1) afforded the title product.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:23])([C:14]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])=[O:15])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:7]([CH3:23])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24])[C:14]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCOCCO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCOCCO)=C(C)C1=O

Procedure:
Oxidation as described in protocol B, using 98.1 mg (0.305 mmol) of 6-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 368 mg CAN (0.671 mmol) yielded 2-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Oc2cccc(CO)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2cccc(COS(C)(=O)=O)c2)cc1
Reaction time: 19 h
Yield: 89 %

Procedure:
To a solution of the obtained (3-(4-methoxy-phenoxy)-phenyl)-metanol (2.0 g, 8.73 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.81 mL, 10.5 mmol) and triethylamine (1.46 mL, 10.5 mmol) on an ice bath, and the solution was stirred for 19 hours. The reaction solution was diluted with dichloromethane, washed with an aqueous solution of 5% sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain methanesulfonic acid 3-(4-methoxy-phenoxy)benzyl ester (2.49, 89%) as a pale brown oil.
Reaction SMILES: [CH3:1][C:2]([NH:15]C(=O)C)([CH3:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.Cl.[OH-].[Na+]>O>[CH3:14][C:2]([NH2:15])([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: CC(=O)NC(C)(C)Cc1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)Cc1ccc2ccccc2c1
Yield: 88.5 %

Procedure:
To N-[2-methyl-1-(naphthalen-2-yl)propan-2-yl]acetamide (26 mg) obtained in Step 8 was added 6N hydrochloric acid (2 ml) and the mixture was heated under reflux for 5 hr. The reaction mixture was poured into water, made basic with a 4N aqueous sodium hydroxide solution, and extracted with diethyl ether. The organic layer was washed with water, dried over potassium carbonate and concentrated under reduced pressure to give the title compound (19 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:34]([S:36][C:37]1[N:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41](O)=[CH:42][CH:43]=2)[N:38]=1)[CH3:35]>C1COCC1>[CH2:34]([S:36][C:37]1[N:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41]([O:33][CH:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:26])[CH2:28][CH2:29]3)=[CH:42][CH:43]=2)[N:38]=1)[CH3:35]
Reactant: CCSc1ncc2ccc(O)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCSc1ncc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of triphenylphosphine (2 eq) in THF was added di-terbutylazodicarboxylate (2 eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that was added tert-butyl-4-hydroxypiperidine-1-carboxylate (5 eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 2-(ethylthio) quinazolin-7-ol (1 eq). The mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and purified by flash column chromatography (10% EtOAc/Hexane) to provide product as a white solid in 90% yield. ES/MS m/z 390.1 (MH+).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 36.3 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.75 g) synthesized in Example 35(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.57 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.44 g, 36%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[NH3:16].C(O)C.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[NH2:16]
Reactant: COc1ccc(OC)c2c1CCCC2=O
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1ccc(OC)c2c1CCCC2N
Temperature: 0 °C
Yield: 93 %

Procedure:
3,4-Dihydro-5,8-dimethoxynaphthalen-1(2H)-one (5 g, 24.2 mmol), titanium(IV) isopropoxide (14.2 mL, 48.5 mmol) and 2 M solution of ammonia in ethanol (60.6 mL, 121.2 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min. (1.4 g, 36.4 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 60 mL), the precipitate that formed was filtered off and washed with ethyl acetate (15 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (15 mL×2). The combined organic extracts were washed with 1 M HCl (25 mL). The acidic aqueous extracts were washed with ethyl acetate (50 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (40 mL×3). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to afford 1,2,3,4-tetrahydro-5,8-dimethoxynaphthalen-1-amine as an oil (4.68 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ 6.66 (s, 2H), 4.18 (br tr, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 2.85-2.79 (m, 1H), 2.47-2.38 (m, 1H), 1.90-176 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:16]C)[CH:6]=[CH:7][C:8]=2[C:12]([F:15])([F:14])[F:13])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:16])[CH:6]=[CH:7][C:8]=2[C:12]([F:14])([F:15])[F:13])[N:3]=1
Reactant: COc1ccc(C(F)(F)F)c2cnc(Cl)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C(F)(F)F)c2cnc(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 2-chloro-8-methoxy-5-(trifluoromethyl) quinazoline (1 eq) (See example 51 for synthesis) in DCM was added boron tribromide at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated and residue was treated with ice cold water. Precipitate was filtered, washed and dried in vacuo to provide product as a yellow solid in 78% yield. ES/MS m/z 249.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[OH-].[K+].C1C(=O)N([Br:27])C(=O)C1.O>CN(C=O)C>[Br:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH:10]=2)[NH:14][N:13]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-1H-indazole (1 g, 4.35 mmol) in DMF (13 ml) were added KOH (488 mg, 8.7 mmol) and NBS (1.15 g, 6.48 mmol) at RT. The reaction mixture was stirred for 2 h at RT. Water was added to the reaction mixture and extracted with EtOAc (2×20 ml). Combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated and purified by column using silica (100-200 mesh) and 0-15 EtOAc-hexane to provide 3-bromo-5-(2,6-difluoro-phenyl)-1H-indazole (600 mg, 45% yield). MS (ESI, pos. ion) m/z: 306.9 (M−1).