Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][NH:14][CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]3)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[S:6][C:5]([C:7]23[CH2:15][N:14]([C:35]4[N:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:13][CH:12]2[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]3)=[CH:4][CH:3]=1
Reactant: O=C(NC1=NC2(c3ccc(F)s3)CNCC2CS1)c1ccccc1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NC1=NC2(c3ccc(F)s3)CN(c3ncccn3)CC2CS1)c1ccccc1
Yield: 69.4 %

Procedure:
To a stirred mixture of N-[7a-(5-fluoro-2-thienyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (127 mg, 0.351 mmol) in 1,4-dioxane (7.0 mL) is added diisopropylethylamine (0.184 mL, 1.05 mmol) and 2-chloropyrimidine (402 mg, 3.51 mmol). The solution is heated to reflux for 2 hours then is cooled, diluted with ethyl acetate, (60 mL) and washed with dilute sodium bicarbonate (30 mL, prepared from saturated sodium bicarbonate (15 mL) and water (15 mL), water (30 mL) and brine (30 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel chromatography eluting with dichloromethane/methanol (gradient from 99:1 to 96:4) to give after concentration a residue which is further purified by silica gel chromatography eluting with hexanes/ethyl acetate (gradient from 60:40 to 30:70) to give the title compound (107 mg, 69%). ES/MS (m/e): 440 (M+H).
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].[C:21](=O)([O-])[O-].[K+].[K+].C[C@:28]1([CH:37]=[CH:36][CH:35]=[CH:34][CH2:33]1)[CH2:29][N:30]=[C:31]=[O:32]>O1CCCC1>[C:28]1([C@@H:29]([NH:30][C:31](=[O:32])[O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7]3)[CH3:21])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@]1(CN=C=O)C=CC=CC1
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)N[C@@H](C)c3ccccc3)ccc21
Reaction time: 1 h
Yield: 144.7 %

Procedure:
To 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (1.75 g) in 30 ml of tetrahydrofuran was added potassium carbonate (milled, 0.912 g) followed by (S)-(-)-1-methylbenzyl isocyanate (0.97 g), and the reaction was allowed to proceed for one hour. The reaction mixture was filtered and the filtrate concentrated to yield an oil (3.9 g) which was eluted with 5% methanol in dichloromethane (DCM) on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid 2.6 g, m.p. 78°-80° C.
Reaction SMILES: COC([CH2:5][N:6]1[CH2:10][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[C@H:8]([C:15]([O:17][CH3:18])=[O:16])[CH2:7]1)=O.[CH3:19]C(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]([CH:9]1[CH:8]2[CH2:7][N:6]([CH2:5][C:15]2([O:16][CH3:19])[O:17][CH3:18])[CH2:10]1)=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CN1C[C@@H](C(=O)OC)[C@H](C(=O)OC)C1
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN2CC1C(OC)(OC)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A solution of 1-methoxycarbonylmethyl-trans-3,4-dimethoxycarbonylpyrrolidine (5 g, 19.31 mmol) in toluene (75 ml) was added dropwise over a 1 hour period to a rapidly stirred solution of potassium-t-butoxide (9 g, 80 mmol) in toluene (250 ml) at 130° C. The mixture was refluxed for 4 hours, cooled to room temperature and concentrated hydrochloric acid (75 ml) added dropwise and stirred for 0.25 hours. The organic phase was extracted with further portions of hydrochloric acid (3×50 ml) and the combined aqueous heated at 110° C. for 16 hours. The solvent was then removed in vacuo, the residue dried and taken up into methanol (saturated with hydrogen chloride, 150 ml). The mixture was stirred at room temperature for 24 hours and the solvent removed under vacuum. The residue was dissolved in water (50 ml), basified to pH>10 with potassium carbonate and extracted with dichloromethane (5×150 ml). The combined extracts were dried (Na2SO4) and the residue remaining after removal of the solvents was chromatographed through silica-gel, using dichloromethane/methanol (93:7) as eluant, to give the title ester as a yellow liquid (0.5 g). An analytical sample was prepared as the hydrogen oxalate salt, mp 134.5°-136.5° C. (propan-2-ol); (Found: C, 47.04; H, 6.20; N, 4.50. C10H17NO4.(CO2H)2 requires C, 47.21; H, 6.27; N, 4.59%); δ (360 MHz, CDCl3) 2.44 (1H, dd, J=9.8 and 3.2 Hz), 2.63 (1H, dd, J=12.7 and 3.2 Hz), 2.77 (1H, d, J=12.7 Hz), 2.80-3.10 (5H, m), 3.11 (3H, s, OCH3), 3.24 (3H, s, OCH3), 3.71 (3H, s, CO2CH3).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:42]1([CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C>[N:42]1([CH2:48][CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:55][C:56]2[CH:57]=[CH:58][C:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:60][CH:61]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-piperidin-1-yl-ethyl ester (103 mg, 242 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (40 mg; purity 95%). MS m/z [M+H]+ calc'd for C29H37N5O4, 520.28. found 520.4.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)NC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(=O)NC1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of N-[1-(7-acetyl-5-chloroquinolin-8-yl)piperidin-4-yl]acetamide (0.042 g, 0.12 mmol) and ammonium acetate (0.0936 g, 1.21 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.30 mL, 0.30 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H24ClN4O (M+H)+: m/z=347.2; Found: 347.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([NH:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][CH2:13][NH:14][C:33](=[O:34])[CH2:32][NH:31][C:30]2[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(O)CNc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C(CNc1ccc(Cl)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 190 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A mixture of 3,4-dibenzyloxyphenethylamine (36.2 g) and p-chloroanilinoacetic acid (20 g) was stirred for 3 hours at 190° C. The reaction mixture was dissolved in benzene. The solution was washed with a diluted potassium carbonate aqueous solution and dried. The solvent was distilled off from the benzene solution and the residue obtained was purified by column chromatography on silica gel to give N-[2-(3,4-dibenzyloxyphenyl)ethyl] -2-(p-chloroanilino)acetamide (27.2 g), mp 121° C.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([C:22](O)=[O:23])=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[S:13][CH:14]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1csc2ccccc12
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1csc2ccccc12

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1-benzothiophene-3-carboxylic acid (Maybridge) according to methods A and C; yield 58 mg, 0.17 mmol (56%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=13 Hz, 2H), 2.20 (s, 1H), 2.36 (d, J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.69 (d, J=2 Hz, 4H), 4.47 (s, 1H), 7.38-7.48 (m, 2H), 7.92-7.96 (m, 1H), 8.27 (s, 1H), 8.27-8.32 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+; Anal. C18H20N2OS.HCl.0.13H2O: C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([NH:17][CH:18](O)[CH3:19])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOCC.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(O)NC(=O)OC(C)(C)C
Reactant: Cc1cc(O)ccc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-3-methylphenol (0.187 g; 1.00 mmol), N-Boc aminoethanol (0.39 mL; 2.5 mmol) and PPh3 (0.655 g; 2.5 mmol) in anhyd PhH (5 mL) at 0° C. was added DIAD (0.49 mL; 2.5 mmol), dropwise over 15 min. The mixture was stirred 16 h at room temperature, diluted with Et2O, washed (2×satd Na2CO3, 2×H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless gum, which solidified on standing. LC/MS (method A) tR 2.95 min, m/z 330, 332 (M+H, Br isotopes, 2%), 352, 354 (M+Na, Br isotopes, 40-43%), 230, 232 ([M-Boc]+H, Br isotopes, 100%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH2:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[C:15]([O:29][CH3:30])[CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>>[NH2:11][C:9]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[C:15]([O:29][CH3:30])[CH:14]=2)[C:5]2=[N:6][CH:7]=[C:2]([C:34]#[C:33][CH2:32][CH2:31][OH:35])[CH:3]=[C:4]2[N:10]=1
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)cnc43)cc2OC)cn1
Reactant: C#CCCO
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(C#CCCO)cnc43)cc2OC)cn1

Procedure:
This compound was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine and but-3-yn-1-ol using the procedure described in Example 3-41-2: 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.93 (s, 1H), 7.74 (dd, J=8.5, 2.0 Hz, 1H), 7.41 (s, 1H), 7.08-6.97 (m, 4H), 6.83 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 4.96 (s, 2H), 4.91 (t, J=5.5 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.61-3.57 (m, 2H), 2.56 (t, J=6.5 Hz, 2H) ppm; (M+1)=460.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].C[S:12](C)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: CS(C)=O
Product: N#Cc1c(S)cccc1Cl

Procedure:
The solution of 2,6-dichloro-benzonitrile (20 mmol) in DMSO (dimethyl sulfoxide, 30 mL) was heated to 70° C., followed by addition of Na2S.9H2O portionwise under stirring. The mixture was stirred for 1 hour. TLC monitored the reaction. After the reaction completed, the mixture was cooled and extracted between water and ethyl acetate. The aqueous layer was acidified by hydrochloric acid to pH=3˜4 under stirring. The formed solids were collected by filtration and dried to give 2.3 g of 2-chloro-6-mercapto-benzonitrile (2A). MS (ESI): M++1=170.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CCN(CC)CC.Cl.Cl[CH2:22][CH2:23][N:24]([CH2:32][CH2:33]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCO>[CH2:25]([N:24]1[CH2:32][CH2:33][N:12]([C:10]2[CH:11]=[C:2]([Br:1])[CH:3]=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)[CH2:22][CH2:23]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(Br)cc2cccnc12
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Brc1cc(N2CCN(Cc3ccccc3)CC2)c2ncccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
The free base of bis(2-chloroethyl)-benzlyamine (5.12 g, 19.3 mmol) was prepared by washing the HCl salt with 1 M NaOH (200 mL) and extracting into EtOAc. The resulting organic phases were dried over Na2SO4 and concentrated. To this flask was added 6-bromo-8-amino-quinoline (2.15 g, 9.6 mmol), n-BuOH (100 mL), and Et3N (4 mL, 28.9 mmol). The resulting reaction mixture was stirred at 100° C. overnight. TLC analysis showed starting amine was still present, therefore an additional portion of bis(2-chloroethyl)-benzylamine hydrochloride (5 g) was added. The reaction was heated an additional 72 hours. The cooled reaction mixture was quenched with 1 M NaOH (200 mL) and extracted into EtOAc (3×200 mL). The organic fractions were combined, dried over Na2SO4, and concentrated. The resulting gold oil was purified three times by column chromatography (40% EtOAc/hexanes) affording 1.2 g (33%) of a viscous orange oil which solidified upon standing: mp 65-68° C., MS (+) APCI m/z 382 [M+H]+.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:2][C:1]1[S:35][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][N:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: Cc1nnc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of N-{2-[(2-acetylhydrazino)carbonyl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.65 g), Lawesson's reagent (0.76 g) and tetrahydrofuran (30 mL) was stirred at 50° C. overnight. The resulting crystals were filtrated, washed with tetrahydrofuran, and dried to give the title compound (0.45 g, yield 71%) as colorless crystals. melting point 308-309° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:17][C@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]([F:38])[F:37])=[CH:30][CH:29]=3)[CH:21]=2)([O:18][CH3:19])[C@H:15]([OH:39])[C@@H:14]([OH:40])[C@@H:13]1[OH:41])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1.CN(C)C=O>[CH2:42]([O:41][C@H:13]1[C@H:14]([O:40][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]([O:39][CH2:16][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([F:38])[F:37])=[CH:32][CH:33]=3)[CH:21]=2)([O:18][CH3:19])[O:17][C@@H:12]1[CH2:11][O:10][Si:3]([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 200.1 %

Procedure:
60% NaH (1.9 g, 47.21 mmol) and 15 mL THF were added into a 100 mL reaction flask and cooled to 0° C., followed by dropwise addition of (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 12f (4.96 g, 8.43 mmol) in THF (18 mL) within 10 minutes at 0° C. The reaction mixture was stirred for 30 minutes. Then a solution of benzyl bromide (7.21 g, 42.15 mmol) in N,N-dimethyl formamide (10 mL) was dropwise added before the reaction mixture was warmed and stirred for 16 hours at room temperature. Thereafter, the reaction mixture was partitioned after 200 mL ethyl acetate, saturated sodium bicarbonate (70 mL) and water (50 mL) were added. The organic extract was washed with 0.01 N hydrochloric acid (60 mL) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 12g (7.25 g, pale yellow liquid), which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH3:19][O:20][SiH:21]([O:24][CH3:25])[O:22][CH3:23].[SiH4]>[Pt]>[CH3:19][O:20][Si:21]([CH2:3][CH2:2][CH2:1][C:4]1[C:13]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O:24][CH3:25])[O:22][CH3:23]
Reactant: CO[SiH](OC)OC
Reactant: C=CCc1ccc2cccnc2c1O[Si](C)(C)C
Agent: [Pt]
Agent: [SiH4]
Product: CO[Si](CCCc1ccc2cccnc2c1O[Si](C)(C)C)(OC)OC
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To a one-ounce glass vial containing 6.7 gms (0.026 moles) of 7-allyl-8-trimethylsiloxyquinoline was added 6.34 gms (0.052 moles) of trimethoxysilane and a trace of platinum catalyst (H2PtCl6 4H2O). Some bubbling occurred. The reaction was warmed at 40° C. for 8 hours during which time the reaction was monitored by GLC. A GLC after 3 days at 40° C. showed a small amount of the starting silane and a large product peak corresponding to ##STR17## Analysis showed nd25 =1.525. Infra-red analysis showed the disappearance of the C=C peak. H'NMR:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>ClCCl>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2C)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (8.2 g, 24.28 mmol) and DIPEA (10.60 mL, 60.69 mmol) were dissolved in dichloromethane (100 mL). Methyl carbonochloridate (2.257 mL, 29.13 mmol) was added and the reaction stirred at room temperature for 1 h. DCM (100 mL) was added. The organic phase was washed twice with 1 M HCl and water, dried over Na2SO4 and evaporated to yield dimethyl 2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (8.9 g, quant.). MS m/z 360 (M+H)+
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:13])=[C:6]([C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])[NH2:7])#N.S(=O)(=O)(O)[OH:15].[C:19](=O)([O-])[O-:20].[Na+].[Na+]>CO.O>[NH2:7][C:6]1[C:5]([CH3:13])=[C:4]([CH2:3][C:1]([O:20][CH3:19])=[O:15])[C:10]([CH3:11])=[CH:9][C:8]=1[CH3:12]
Reactant: Cc1cc(C)c(CC#N)c(C)c1N
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1c(C)cc(C)c(N)c1C
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 3-cyanomethyl-2,4,6-trimethylaniline (see Example 14, procedure C) (5 g, 28.7 mmol) in methanol (30 mL) was added concentrated sulfuric acid (30 mL) with cooling. The resulting mixture was heated under reflux for 8 h before it was allowed to cool to rt and diluted with water (100 mL). The mixture was stripped off methanol and the residue was basified with sodium carbonate and then extracted with ethyl acetate. The organic layer was worked up and concentrated as usual to give the desired compound as an oil (5.2 g, 88%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[CH:5]2.[NH2:14][C@@H:15]([CH3:24])[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:17][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([NH2:14])[CH3:24])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)([CH3:13])[CH3:12]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: CC(C)n1ncc2cc(I)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: CC(C)n1ncc2cc(O[C@H](c3ccccc3)[C@H](C)N)ccc21
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A mixture of 5-iodo-1-isopropyl-1H-indazole (30c, 461 mg, 1.26 mmol), (1R,2S)-2-amino-1-phenylpropan-1-ol (286 mg, 1.89 mmol), copper (I) iodide (25 mg, 130 μmol), and cesium carbonate (1.45 g, 3.8 mmol) in butyronitrile (5 ml) was stirred at 125° C. for 2 h. Then the mixture was cooled to room temp., the inorganic material was removed by filtration and washed with ethyl acetate. The combined organic solutions were concentrated i. vac., and the product purified by flash chromatography on silica gel (ethyl acetate/methanol). Yield 200 mg (51%) of a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-4-nitro-benzaldehyde (4.68 g, 28 mmol) is dissolved in DMF (27 mL) and to the solution is added with stirring powdered potassium carbonate (4.27 g, 30.1 mmol) and benzyl bromide (3.34 mL, 28.1 mmol). The mixture is stirred at RT overnight, diluted with water (200 mL) and extracted three times with EtOAc. The organic extracts are washed with 10% potassium carbonate and brine, dried over anhydrous MgSO4, decolorized with charcoal, filtered and evaporated to give 3-benzyloxy-4-nitro-benzaldehyde as an oil which is used in the next step without purification.