Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:40]2[CH2:45][C@H:44]([CH3:46])[O:43][C@H:42]([CH3:47])[CH2:41]2)=[C:28]([F:39])[C:29]([F:38])=[C:30]([C:32](=O)[C:33]([F:36])([F:35])[F:34])[CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:49][OH:50]>C(O)C>[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:40]2[CH2:41][C@H:42]([CH3:47])[O:43][C@H:44]([CH3:46])[CH2:45]2)=[C:28]([F:39])[C:29]([F:38])=[C:30]([C:32](=[N:49][OH:50])[C:33]([F:36])([F:35])[F:34])[CH:31]=1)([C:20]([CH3:21])([CH3:23])[CH3:22])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)(F)F)c(F)c2F)C[C@H](C)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)C(F)(F)F)c(F)c2F)C[C@H](C)O1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
Pyridine (2597 μl, 32.11 mmol) was added to a mixture of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2,2,2-trifluoroethanone (Intermediate 130, 1900 mg, 3.21 mmol) and hydroxylamine hydrochloride (223 mg, 3.21 mmol) in 50 ml of ethanol and the solution was heated at 80° C. for 40 hours. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), and concentrated to give the crude title compound (1.95 g, 98%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1.C1C2NC3C(=CC=CC=3)C=2C(OC(C)(C)C(O)=O)=CC=1.Cl[CH2:46][C:47]1[CH:65]=[CH:64][C:50]([O:51][CH2:52][C:53]2[N:54]=[C:55]([C:59]3[O:60][CH:61]=[CH:62][CH:63]=3)[O:56][C:57]=2[CH3:58])=[C:49]([O:66][CH3:67])[CH:48]=1.ClCC1C=CC(OCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1>>[O:60]1[CH:61]=[CH:62][CH:63]=[C:59]1[C:55]1[O:56][C:57]([CH3:58])=[C:53]([CH2:52][O:51][C:50]2[CH:64]=[CH:65][C:47]([CH2:46][N:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:16]([OH:18])=[O:17])[C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:48][C:49]=2[O:66][CH3:67])[N:54]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=C(O)C(Oc1cccc2[nH]c3ccccc3c12)c1ccccc1
Agent: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(Cn2c3ccccc3c3c(OC(C(=O)O)c4ccccc4)cccc32)ccc1OCc1nc(-c2ccco2)oc1C

Procedure:
The subject compound was prepared by performing the same operation as that of the example 3 by using 2-(9H-carbazole-4-yloxy)-2-phenylacetic acid prepared by the reference 21 instead of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid used in the example 3, and using 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-2-(furan-2-yl)-5-methyloxazole prepared by the reference 2 instead of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[OH:17])=[CH:12][C:11]=2[C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3C2CCCCO2)=[CH:5][CH:4]=1.Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH:16]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[OH:17])=[CH:12][C:11]=2[C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][NH:32]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(O)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(C(O)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
(6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)(4-(methylsulfonyl)phenyl)methanol (the crude material from the previous step) was suspended in MeOH (5.0 mL) and aqueous hydrochloric acid (5N, 0.50 mL, 2.5 mmol) was added. The reaction was stirred at room temperature for about 2 h, and then was diluted with DCM and MeOH. After 3.5 h, the suspension was filtered. Neither solid nor filtrate was >95% pure by HPLC, so they were combined, concentrated, treated with water, and filtered. The solid was collected, treated with DMSO and TFA, and filtered through a Celite® (diatomaceous earth) pad. The filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min with a total flow rate of 100 mL/min.) to give (6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)(4-(methylsulfonyl)phenyl)methanol (122.4 mg, 56% yield over two steps). 1H NMR (d6-DMSO, 400 MHz) includes δ 12.62 (br s, 1H), 9.84 (br s, 1H), 8.62 (s, 1H), 8.52 (d, J=2.54 Hz, 1H), 8.29 (d, J=2.15 Hz, 1H), 8.16 (dd, J=8.71 Hz, 2.64 Hz, 1H), 7.90 (d, J=8.22 Hz, 2H), 7.73 (d, J=8.22 Hz, 2H), 6.84 (d, J=8.80 Hz, 1H), 5.91 (s, 1H), 3.84 (s, 3H), 3.17 (s, 3H), 2.84 (s, 3H). m/z (ESI, pos. ion) 518 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)(=[O:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(-c2cccc(-n3c4c(c5cc(C)ccc53)CN(C)CC4)c2)cn1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-acetamidopyridine-5-boronic acid pinacol ester (147 mg, 0.560 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield N-(5-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-yl)acetamide. 1H NMR (TFA salt, CD3OD) d (ppm): 8.6 (s, 1H), 8.18 (s, 2H), 7.8 (d, 1H), 7.62-7.77 (m, 2H), 7.42 (d, 1H), 7.3 (s, 1H), 7.17 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.42 (d, 1H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.O>CN(C)C=O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Potassium carbonate (4.1 g) and (3-bromopropoxy)-tert-butyldimethylsilane (4.1 g) were added to a solution of 4-bromothiophenol (3.0 g) in N,N-dimethylformamide, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→20:1) to give the title compound as a colorless oil (5.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([NH:15][C:16]([NH2:18])=[S:17])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([NH:15][C:16](=[NH:18])[S:17][CH3:27])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(NC(N)=S)on1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSC(=N)Nc1cc(C(C)c2ccc(-c3ccccc3)c(F)c2)no1

Procedure:
3-[1-(2-Fluoro-biphenyl-4-yl)-ethyl]-isoxazol-5-yl-thiourea (Japanese Patent Unexamined Publication No. 63-152368) (3.03 g) was dissolved in N,N-dimethylformamide (90 ml), followed by adding thereto methyl iodide (1.51 g) and potassium carbonate (0.86 g), and the resulting mixture was stirred at 40° C. for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (2.67 g).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3([C:22](=[O:47])[NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][C:29]([C:33]6[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([F:40])[C:34]=6[C:41]6[N:45]=[C:44]([CH3:46])[O:43][N:42]=6)=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[CH2:21][O:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[Cl:39][C:37]1[CH:36]=[C:35]([F:40])[C:34]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[C@@H:24]([NH:23][C:22]([C:18]2([NH2:17])[CH2:19][O:20][CH2:21]2)=[O:47])[CH2:25][CH2:26]3)[CH:38]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)COC2)no1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (3-{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-ylcarbamoyl}-oxetan-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester (intermediate A-12) (2.94 g, 4.42 mmol) in MeCl2 (50.0 ml) was added piperidine (4.38 ml) and the mixture was stirred at room temperature for 15 h. The colorless solution was concentrated to dryness under high vacuum at RT. The remaining residue was purified by chromatography (silica gel; MeCl2/MeOH 100:0-95:5) and the title compound was obtained as light brown oil (1.09 g, 56%). MS: 443.1 (MH+, 1Cl).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])N(C1CCNCC1)[C:8]2=[O:24])([CH3:3])[CH3:2].CO.C=O.[C:29]([BH3-])#[N:30].[Na+]>C1COCC1.CC(O)=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])[CH:8]([CH:7]1[CH2:11][CH2:10][N:30]([CH3:29])[CH2:5][CH2:6]1)[C:8]2=[O:24])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCNCC1)C2=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)C(C1CCN(C)CC1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 5-isopropoxy-6-nitro-2-piperidin-4-yl-isoindole-1,3-dione generated in the previous step in THF (5 mL) and methanol (5 mL) are added formaldehyde (30 uL, 0.4 mmol) and 2 drops of AcOH sequentially. The reaction mixture is stirred at room temperature for 1 h, then sodium cyanoborohydride (50.4 mg, 0.8 mmol) is added in one portion and the resulting mixture is stirred for an additional 30 min. The reaction is quenched by the addition of saturated aqueous NH4Cl followed by concentration in vacuo to give an oily residue. This oil is partitioned between EtOAc and brine. The organic extract is dried over Na2SO4, filtered and concentrated. Silica gel chromatography (5% MeOH in DCM) affords 5-isopropoxy-2-(1-methyl-piperidin-4-yl)-6-nitro-indan-1,3-dione; MS m/z 347.2 (M+1).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([O:46]CC1C=CC=CC=1)=[O:45])[CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[Pd]>[C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([OH:46])=[O:45])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)[C@@H](C)O
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)[C@@H](C)O
Yield: 91.3 %

Procedure:
Dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamate (48 g) in demethylformamide (500 ml) was hydrogenated over palladium black (1 g) at room temperature at 1 atmospheric pressure. After the theoritical amount of hydrogen was adsorbed, dimethylformamide was removed under reduced pressure. The residual crude crystal was recrystallized from ethanol to give N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamic acid (35.5 g).
Reaction SMILES: Br.C(OC([N:12]1[CH2:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:14]=2[CH2:13]1)=O)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C>[C:28]1([S:25]([N:15]2[C:14]3[CH2:13][NH:12][CH2:24][CH2:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccccc23)C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1c2c(c3ccccc31)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
33% hydrogen bromide in glacial acetic acid (20.7 ml) was added to a suspension of the product from stage 2 (4.14 g, 9.27 mmol) in glacial acetic acid (20.7 ml) and the mixture was stirred at room temperature for 1 h. The mixture was poured into diethyl ether (500 ml). The hydrobromide which had precipitated out was filtered off with suction, washed with diethyl ether and dried over potassium hydroxide in a desiccator. Saturated potassium carbonate solution (100 ml) was added to the salt (3.60 g) and the resulting mixture was extracted with methylene chloride (3×25 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12](Br)=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:29](=[O:32])([O-])[O-].[Cs+].[Cs+]>C(O)C(F)(F)F>[CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:32][CH2:29][C:15]([F:18])([F:17])[F:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F)C1CC1
Agent: [Cs+]
Solvent: OCC(F)(F)F
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Temperature: 80 °C
Yield: 153.9 %

Procedure:
A mixture of 0.050 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide and 0.050 g cesium carbonate in 0.5 ml trifluoroethanol was heated to 80° C. for 20 min. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine evaporated and the crystalline residue was triturated under heptane to yield 0.040 g of the title compound as off white powder. MS (M−H) at 496.4 and 498.4.
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.P([N:46]=[N+:47]=[N-:48])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([C@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@@H]2O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (1S)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.0 g) and diphenyl phosphorazidate (0.65 ml) was dissolved in toluene (10 ml). The mixture was cooled to 0° C. under N2, and neat 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.45 ml) was added. The reaction mixture was stirred for 2 hours at 0° C. then at 20° C. for 16 hours. The resulting mixture was washed with water and 1N-HCl. The organic layer was concentrated in vacuo and purified by silica gel chromatography to give (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (950 mg). MS (m/z): (400 (M+ +() IR (Neat): 2100 cm-1NMR (CDCl3, δ): 1.10 (9H, s), 1.8-2.2 (4H, m), 2.6-3.1 (2H, m), 4.5-4.7 (1H, m), 6.3-6.4 (1H, m), 6.7-7.0 (2H, m), 7.1-7.8 (10H, m)
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[CH3:18]O>>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=1
Reactant: CO
Reactant: COc1ccc(CCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Thionyl chloride (3.1 ml, 42.5 mmol) was added slowly to methanol (30 ml) with stirring under cooling with a Dry Ice/methanol bath. After allowing the reaction to warm to room temperature, 3-(4-methoxyphenyl) propionic acid (5 g, 27.7 mmol) was added and stirred for an additional 1 hour. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed twice with a saturated aqueous solution of sodium bicarbonate, then once with a saturated aqueous solution of sodium chloride. After drying over unhydrous sodium sulfate, the solvent was evaporated in vacuo to produce a pale yellow crystal in an amount of 5.29 g (yield, 98%).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:3]1.Cl>CO.O1CCOCC1>[F:21][C:2]1([F:1])[CH2:7][CH2:6][NH:5][CH:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC1(F)CCNC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4,4-difluoro-2-phenylpiperidine-1-carboxylate (0.17 g, 0.57 mmol) in methanol (5 mL) was added 4M hydrogen chloride in dioxane (5 mL). The reaction mixture was stirred at room temperature for 4 hours then concentrated and the residue was triturated with diethyl ether. The white solid was collected by filtration and dried to give 4,4-difluoro-2-phenylpiperidine as the hydrochloride salt (93 mg, 70%). GC-MS (EI) for C11H13F2N: 197 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[N:19]1([C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:7]3[N:8]=[C:9]4[NH:10][C:24]([C:26]5[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=5)[C:29]#[N:30])=[N:3][C:4]4=[CH:5][CH:6]=3)[CH2:12]2)=[O:18])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: N#Cc1cccc(C=O)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Reaction time: 20 h
Yield: 66.6 %

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3) (50 mg, 0.15 mmol) and 3-formylbenzonitrile (34 mg, 0.31 mmol) in ethanol (2 mL) were added sodium dithionite (52 mg, 0.4 mmol), and water (0.5 mL). After 20 h at 80° C., the mixture was concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure and the resulting residue was purified by preparative TLC to afford (R)-3-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzonitrile as a yellow solid (40 mg, 81%). MS (ES+APCI) (M+H) 401.0; HPLC retention time 4.016 min (Method I).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:27]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:15]3[CH:7]=[C:8]([CH3:27])[S:9][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2ncnc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl
Reactant: c1cn[nH]c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 5-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: ClC1C=C2C(=CC=1)OC(C)(C)C(O)C2CS(N[CH2:20][C:21]([O:23][CH3:24])=[O:22])(=O)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][C:31]([CH3:37])([CH3:36])[CH:30]([OH:38])[CH:29]2[NH:39][S:40]([CH3:43])(=[O:42])=[O:41].[H-].[Na+].BrCC(OC)=O>CN(C=O)C.CC(=O)OCC>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[O:32][C:31]([CH3:37])([CH3:36])[CH:30]([OH:38])[CH:29]2[N:39]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: COC(=O)CNS(=O)(=O)CC1c2cc(Cl)ccc2OC(C)(C)C1O
Reactant: CC1(C)Oc2ccc(Cl)cc2C(NS(C)(=O)=O)C1O
Agent: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C1c2cc(Cl)ccc2OC(C)(C)C1O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl [(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonylamino]acetate A solution of 3.0 g (10 mmol) of N-(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonamide was added dropwise to a solution of 0.33 g (11.3 mmol) of 80 percent sodium hydride in 25 ml of DMF and the mixture was additionally stirred at RT for 1 h. 1.53 g (10 mmol) of methyl bromoacetate were then added, the mixture was stirred overnight at RT and then the solvent was stripped off in vacuo. The residue was taken up in EA and water, the organic phase was concentrated and the product was purified by chromatography on silica gel using cyclohexane/ethyl acetate 9:1. 2.0 g of methyl [(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)-methanesulfonylamino]acetate were obtained; m.p. 148-150° C.