Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]2[S:23][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])=[N:21][C:20]=2[CH3:30])=[O:18])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]2[S:23][C:22]([N:24]3[CH2:28][CH2:27][CH:26]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=4)[C:25]3=[O:29])=[N:21][C:20]=2[CH3:30])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1nc(N2CCC(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use 1-(bromomethyl)-4-fluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene to react with N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 36% yield: mp 196-197° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 2H), 7.13 (dd, J=8.6, 5.6 Hz, 2H), 7.06-6.90 (m, 4H), 6.03 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.06-3.95 (m, 1H), 3.95-3.70 (m, 1H), 3.29-3.10 (m, 1H), 3.05-2.92 (m, 1H), 2.88-2.70 (m, 1H), 2.60 (s, 3H), 2.32-2.17 (m, 1H), 2.00-1.80 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.8, 176.3, 162.3, 161.8, 155.4, 152.9, 133.8, 133.7, 130.4, 129.6, 118.5, 115.7, 115.5, 45.9, 44.4, 43.4, 35.6, 24.2, 17.3; MS (ES+) m/z 442.2 (M+1).
Reaction SMILES: [ClH:1].FC1C=CC(C(=O)CCCN2CCC(C(O)(C3C=CC=CC=3)C3C=CC=CC=3)CC2)=CC=1.Cl.O[C:36]([CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH2:57][C:58]([C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][CH:61]=2)=[O:59])[CH2:51][CH2:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[ClH:1].[C:43]1([C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:49]2[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][CH2:57][C:58]([C:60]3[CH:61]=[CH:62][C:63]([O:66][CH3:67])=[CH:64][CH:65]=3)=[O:59])[CH2:53][CH2:54]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COc1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Product: COc1ccc(C(=O)CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
By the procedure of Example 3 only substituting for 4'-fluoro-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone hydrochloride an appropriate amount of 4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]-4'-methoxybutyrophenone hydrochloride, the desired product was obtained upon recrystallization from methanol-benzene, M.P. 185.5°-187° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[C:19]([C:20]([O-:22])=O)=[C:18]([N:23]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:17]=[C:16]([S:41][CH3:42])[N:15]=1.O>O1CCCC1>[Cl:13][C:14]1[C:19]2[C:20](=[O:22])[CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34][CH2:33][N:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:18]=2[N:17]=[C:16]([S:41][CH3:42])[N:15]=1
Reactant: CCOC(=O)CCCN(Cc1ccc(OC)cc1)c1nc(SC)nc(Cl)c1C(=O)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCN(Cc2ccc(OC)cc2)c2nc(SC)nc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
To an ice-cooled solution of diisopropylamine (28.16 mL, 198.96 mmol) in tetrahydrofuran (400 mL) was added n-BuLi (15% in hexane, 82.5 mL, 192.93 mmol) dropwise and the mixture was then stirred at the 0° C. for 45 min. The reaction mixture was cooled to -78° C. and 4-chloro-6-((4-ethoxy-4-oxobutyl)(4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (29.0 g, 60.17 mmol) in tetrahydrofuran (300 mL) was added to the mixture dropwise over 45 min. and the reaction mixture was stirred at −78° C. for 15 min and ice cooled water (1 L) was added to the reaction mixture at same temperature. The reaction mixture was then warmed to room temperature and extracted with EtOAc (500 mL×2). The combined organic layer was washed with water (1 L), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford ethyl 4-chloro-9-(4-methoxybenzyl)-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]azepine-6-carboxylate (23.5 g); which was used in the next step without any purification. 1HNMR (400 MHz, CDCl3): δ 7.19 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 5.17 (d, J=14.8 Hz, 2H), 4.23-4.16 (d, J=14.8 Hz, 2H), 4.12-4.06 (m, 1H), 3.85-3.83 (m, 1H), 3.80 (s, 3H), 3.45-3.33 (m, 2H), 2.72-2.64 (m, 1H), 2.47 (s, 3H), 2.29-2.22 (m, 1H), 1.17 (t, J=7.2 Hz, 3H). LCMS [M+H]: 436
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[CH2:14]>CO>[CH2:17]([O:16][P:15]([CH2:13][CH2:14][NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: C=CP(=O)(OCC)OCC
Solvent: CO
Product: CCOP(=O)(CCNCCCNC(=O)OC(C)(C)C)OCC
Reaction time: 48 h
Yield: 81.3 %

Procedure:
To a solution of 3-(t-butyloxycarbonylamino) propanamine (77 g, 0.44 mole) in methanol (500 mL) was added diethyl vinylphosphonate 97% (75 g, 0.44 mole; Aldrich 11, 613-0) under nitrogen and kept in a water bath at ~20° C. for 48 hr. The reaction mixture was concentrated in vacuo and the residue (~160 g) was put on a pad of "Florisil" (3"×6") and eluted with methylene chloride/hexane 1:1, methylene chloride and finally 10% methanol/methylene chloride to give the title compound as a colorless oil (121 g, 80%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@H:4]1[OH:8].Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(=O)(O)[O-].[Na+]>O>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[N:6]1[CH2:7][C:3]([CH3:9])([CH3:2])[C@H:4]([OH:8])[CH2:5]1
Reactant: Clc1nc2ccccc2s1
Reactant: CC1(C)CNC[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)CN(c2nc3ccccc3s2)C[C@H]1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a slurry of 600 mg (4 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 670 mg (4 mmol) of 2-chlorobenzthiazole was added a solution of 1.0 g (12 mmol) of sodium bicarbonate in water. The reaction mixture was heated to 80° C. and stirred overnight. It was then diluted with water, the resulting mixture was extracted with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 950 mg (96%) of (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol. 1H-NMR (300 MHz, DMSO-6): δ 7.76 (d, J=8 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 1H), 5.27 (d, J=5 Hz, 1H), 3.84–3.77 (m, 2H), 3.39–3.25 under DMSO peak (m, 3H), 1.05 (d, J=8 Hz, 6H); ES-LCMS m/z 249 (M+H).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[NH:35][CH:36]=[C:37]1[C:42](=[O:43])OC(C)(C)OC1=O.C(=O)=O>CC(C)=O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]2[C:28]=1[NH:35][CH:36]=[CH:37][C:42]2=[O:43]
Reactant: COc1ccc(Br)c(NC=C2C(=O)OC(C)(C)OC2=O)c1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(Br)c2[nH]ccc(=O)c12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 75.7 %

Procedure:
Dowtherm A (30 ml) was heated to reflux and enamine (a) (10 g) was added portionwise (CAUTION—vigorous evolution of CO2 and acetone) over 2 minutes. Heating was continued for a further 2 minutes then the mixture was allowed to cool to room temperature. Filtration and drying in vacuo afforded a brown solid (5.4 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:34]1C=C(S(Cl)(=O)=O)C=C[CH:39]=1>>[CH2:34]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:16][CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:39]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=469.0 (M−H), was prepared in analogy to example 57, steps 1 to 6. Step 5 was performed using 3-chloro-benzenesulfonyl chloride, yielding 4-{[1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][O:2][C:3](OC)(OC)[CH3:4].[NH2:9][C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>>[CH3:1][O:2][C:3](=[N:9][C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: COC(C)(OC)OC
Product: COC(=O)c1ccc(C(=O)OC)c(N=C(C)OC)c1

Procedure:
3.8 g (32 mmmol) of 1,1,1-trimethoxyethane and 1.5 g (7.17 nmuol) of dimethyl 2-aminoterephthalate are introduced into a reactor. The medium is stirred and refluxed for 5 h, and then concentrated to dryness at 50° C. under a vacuum of less than 1 mm Hg. 1.4 g of a thick brown oil are obtained.—TLC (99/1 CH2Cl2/MeOH): Rf=0.7 -0.8.
Reaction SMILES: C(OC([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:16][C:10]=2[C:9]=1[O:24]C(=O)C(C)(C)C)=O)CCC.[OH-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[C:19]([CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[S:12][CH:8]=[C:9]([OH:24])[C:10]=2[CH:16]=1)([OH:21])=[O:20]
Reactant: CCCCOC(=O)c1sc2ccc(OCC(=O)OCC)cc2c1OC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)COc1ccc2scc(O)c2c1
Yield: 80 %

Procedure:
1.96 g (4.5 mmol) VIII and 2.70 g (67.5 mmol) NaOH were heated under reflux for 15 h in 300 ml degassed water. The pH was then adjusted to pH 1 with concentrated HCl and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4. Flash chromatography (200 g SiO2, ethyl acetate:acetic acid=100:1, pre-adsorption: 10 g SiO2/ethanol) yielded 801 mg (3.6 mmol, 79%) IX.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].S(OC)(O[CH3:15])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1C(C)C

Procedure:
2-Isopropylphenol (300 g), 262 ml of dimethyl sulfate, and 1500 g of potassium carbonate in 1 liter of acetone are stirred mechanically and refluxed for 61/2 hours. The mixture is filtered and the filter cake washed with acetone. The combined filtrate is stripped, the residue is redissolved in ether, then extracted with 2N sodium hydroxide (twice) and brine (once). The ether is dried, filtered, and stripped to leave an oil which is distilled under high vacuum to afford 2-isopropylanisole, b.p. 39°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[C:29]([OH:30])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[C:22]([Cl:31])[CH:21]=2)[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 57.6 %

Procedure:
To the suspension of N-[(3-aminophenyl)(5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide (150 mg, 0.35 mmol) in methylenechloride (4 ml) cooled to 0 C was added DIEA (50 mg, 0.38 mmol) followed by acetylchloride (32.4 mg, 0.42 mmol). Purification by flush chromatography (eluent 30% acetone/DCM) afforded 96 mg (57%) of N-[[3-(acetylamino)phenyl](5-chloro-8-hydroxyquinolin-7-yl)methyl]-2-phenoxyacetamide as a white solid.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[F:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C@@H:34]1[CH2:44][CH2:43][C:42](=O)[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C@H:35]1[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>C1(C)C=CC=CC=1>[C:49]([O:48][C:47]([NH:46][C@@H:35]1[C:36]2[C:37](=[N:38][CH:39]=[CH:40][CH:41]=2)/[C:42](=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2])/[CH2:43][CH2:44][C@H:34]1[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[F:26])=[O:53])([CH3:51])([CH3:52])[CH3:50]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C1\CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2cccnc21
Yield: 58.8 %

Procedure:
A mixture of (carbethoxymethylene)triphenylphosphorane (0.214 g, 0.614 mmol) and tert-butyl (5S,6S)-6-(2,3-difluorophenyl)-9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.199 g, 0.512 mmol) in toluene (5 mL) was heat to reflux for 18 h. The solvent was removed via vacuum and the crude residue was loaded onto a silica gel column directly. Purification was performed by elution with ethyl acetate in hexane from 0 to 65% to afford the desired product (138 mg, 59%): MS(ESI)[M+H+]=459.22; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.53 (1H, dd, J=4.8, 1.3 Hz), 7.70 (1H, d, J=7.5 Hz), 7.32 (1H, dd, J=7.8, 4.8 Hz), 7.15-7.24 (1H, m), 7.05-7.13 (2H, m), 6.39 (1H, t, J=2.3 Hz), 5.21-5.31 (1H, m), 4.89-4.99 (1H, m), 4.19 (2H, q, J=7.1 Hz), 3.32-3.43 (1H, m), 3.17-3.32 (1H, m), 3.12 (1H, d, J=2.3 Hz), 1.87 (2H, d, J=4.5 Hz), 1.14-1.38 (13H, m).
Reaction SMILES: CCCCCC.[Li]CCCC.[CH3:12][Si:13]([CH3:28])([CH3:27])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>C1COCC1>[CH3:12][Si:13]([CH3:28])([CH3:27])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[C:19]1[B:29]([OH:34])[OH:30]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2cccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1c(B(O)O)cc2cccnc21
Temperature: -45 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A hexane solution of n-BuLi (60 mL, 150.97 mmol) was added slowly to a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (25.0 g, 100.65 mmol) in dry THF (200 mL) at −70° C. under N2 protection. The mixture was stirred at −45° C. for 2 hour. After (i-PrO)3B (30.29 g, 161.03 mmol) was added, the mixture was stirred overnight warming to RT. Then the reaction mixture was quenched with 1M aqueous HCl and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and the solvent was concentrated in vacuo under reduced pressure. The crude product was purified using column chromatography (petroleum ether:EtOAc=5:1) to provide the product of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (14.4 g, yield: 49%). 1H-NMR (CDCl3, 400 MHz) δ 8.49 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.07 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.21 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.92 (s, 1H), 6.02 (s, 2H), 3.74 (t, J=8.4 Hz, 2H), 1.08 (t, J=8.4 Hz, 2H), 0.04 (s, 9H). MS (M+H)+: 293.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]>C(O)C.[Pt]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11](=[O:13])[CH3:12])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pt]
Solvent: CCO
Product: CC(=O)c1cc(N)ccc1F
Reaction time: 20 h
Yield: 58.3 %

Procedure:
A mixture of 1-(2-fluoro-5-nitro-phenyl)ethanone (7.3 g) and 5% Pt(S)/C (730 mg) in ethanol (50 mL) was hydrogenated at 50 psi for 20 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane) to give the title compound as a solid (3.56 g).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[I:25]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[I:25][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH:7]=2)[NH:3][N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]ncc3c2)CC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]nc(I)c3c2)CC1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
KOH (141.5 mg; 2.52 mmol; 3.8 eq.) pellets were added in small portion during 10 min to a solution of tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate (200 mg; 0.66 mmol; 1.0 eq.) and iodine (0.34 g; 1.33 mmol; 2.0 eq.) in dry DMF (6 mL). The reaction mixture was stirred O/N at RT. It was then poured into a saturated solution of Na2S2O3 (100 mL) and extracted three times with ether. Combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow foam (225 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ 13.41 (brs, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.35 (dd, J=8.7, 1.3 Hz, 1H), 7.20 (s, 1H), 4.26-3.94 (m, 2H), 2.93-2.74 (m, 3H), 1.99-1.70 (m, 2H), 1.67-1.47 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): Rt 5.10 min (purity 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:21]2[CH:9]3[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]3[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CC(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)C.O>C1(C)C=CC=CC=1>[CH3:28][N:29](/[CH:31]=[C:12]1\[CH:8]2[CH2:7][C:6]3[CH2:5][CH2:4][CH2:3][C:2]([CH3:22])([CH3:1])[C:21]=3[CH:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]\1=[O:13])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2CC3=C(C21)C(C)(C)CCC3
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)/C=C1/C(=O)N(C(=O)OC(C)(C)C)C2C3=C(CCCC3(C)C)CC12
Temperature: 110 °C
Yield: 64 %

Procedure:
To a solution of tert-butyl 8,8-dimethyl-2-oxo-3a,4,5,6,7,8b-hexahydro-3H-indeno[1,2-b]pyrrole-1-carboxylate (110 mg, 0.36 mmol) in toluene (2 mL) was added Bredereck reagent ((t-butoxybis(dimethylamino)methane) (0.30 mL, 1.44 mmol). The solution was heated to 110° C. for 5 h. The solution was cooled down to room temperature, and water was added. The solution was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (7/3 to 1/1) to give a white solid (83 mg, 64%). Mp 170-172° C.; LCMS (Method B) RT=1.14 min, 361 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.10 (1H, d, J=1.8 Hz), 5.27 (1H, d, J=8.1 Hz), 3.65 (1H, tt, J=8.1, 1.8 Hz), 2.99 (6H, s), 2.24 (1H, d, J=15.4 Hz), 1.75-1.97 (2H, m), 1.49-1.60 (11H, m), 1.38-1.46 (1H, m), 1.32 (1H, m), 1.19 (3H, s), 0.97 (3H, s) ppm.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:20].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:63][CH2:64][C:65]1[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:21][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([NH:63][CH2:64][C:65]3[CH:66]=[N:67][CH:68]=[CH:69][CH:70]=3)=[O:19])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:20]
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
A mixture of 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.11 g, 0.36 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.23 g, 0.73 mmol), N-hydroxybenzotriazole (0.20 g, 0.15 mmol) and N,N-diisopropylethylamine (0.09 g, 0.73 mmol) in anhydrous tetrahydrofuran (3.0 mL) was stirred at ambient temperature for 15 min, followed by the addition of 3-(aminomethyl)pyridine (0.08 g, 0.73 mmol) in anhydrous tetrahydrofuran (1.0 mL). The reaction mixture was stirred at ambient temperature for 16 h, followed by the addition of saturated sodium bicarbonate solution (2 mL). The mixture was extracted with ethyl acetate (3×3 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The solid was purified by flash chromatography eluted with dichloromethane in methanol (2%) to afford the title compound as a colourless solid (0.12 g, 81%): mp 169-171° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (t, J=5.9 Hz, 1H), 8.49 (s, 1H), 8.42 (d, J=3.7 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.32 (dd, J=7.8, 4.9 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 3.99 (d, J=8.3 Hz, 1H), 3.61-3.47 (m, 3H), 3.20-3.12 (m, 1H), 2.44 (s, 3H), 2.05-1.88 (m, 1H), 1.67-1.55 (m, 1H), 1.37-1.27 (m, 1H); MS (ES+) m/z 409.0 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]([NH2:34])[CH2:31][CH2:30][CH2:29]2>>[CH2:1]([C:3]1[C:4]([NH:34][CH:32]2[C:33]3[C:28](=[CH:27][CH:26]=[CH:25][C:24]=3[O:23][CH3:22])[CH2:29][CH2:30][CH2:31]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: COc1cccc2c1C(N)CCC2
Product: CCc1cnc(CC)c(NC2CCCc3cccc(OC)c32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.63, 7.22, 6.78, 5.40, 4.31, 3.71, 2.86-2.65, 2.53-2.38, 1.88-1.67, 1.32, 1.21; HRMS (FAB) calcd for C19H25N3O+H 312.2076, found 312.2077.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16].[BH3-]C#N.[Na+].O.[OH-].[Na+]>CC(O)=O.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: OCCCC#Cc1cc2cc[nH]c2cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: OCCCC#Cc1cc2c(cc1F)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 109 mg (0.5 mmol) 5-(6-Fluoro-1H-indol-5-yl)-pent-4-yn-1-ol in 3 ml AcOH/TFA 2:1 was cooled to 0° C., treated with NaCNBH3 and stirred for 1 hour at room temperature. The mixture was poured into icy water, made strongly alkaline by the addition of 2M NaOH, and extracted with EtOAc. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2/MeOH 49:1 gave 80 mg (73%) of 5-(6-Fluoro-2,3-dihydro-1H-indol-5-yl)-pent-4-yn-1-ol as a colorless oil, MS: 220 (MH+).