Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:30])[C:3]([NH:5][C@@H:6]([CH:27]([CH3:29])[CH3:28])[C:7]([N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[CH2:11][C@H:10]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:8])=[O:4].[O:31]1CC(O)O[CH2:33][CH:32]1O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:21]1([NH:20][C:18]([C@H:10]2[N:9]([C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:33][CH2:32][OH:31])[CH3:30])[CH:27]([CH3:29])[CH3:28])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Reactant: OC1COC(O)CO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)[C@H](C)NCCO)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 146.2 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-((S)-2-aminopropanamido)-3-methylbutanoyl)-N-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carb ox amide (55 mg, 134 μmol, Eq: 1.00) was combined with MeOH (3 mL) to give a colorless solution. 1,4-Dioxane-2,5-diol (8.87 mg, 73.9 μmol, Eq: 0.55) was added followed by acetic acid (8 μL, 134 μmol, Eq: 1.00) and sodium cyanoborohydride (13 mg, 210 μmol, Eq: 1.5). The reaction was stirred at rt for 4 h and then quenched by dropwise addition of 1 M aqueous HCl. The reaction mixture was basified with 0.1 M aqueous NaOH, extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to give (S)-1-{(S)-2-[(S)-2-(2-Hydroxy-ethylamino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a white solid (49 mg), m/z=454.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH3:18])=[C:16]2[C:11]([CH2:12][CH2:13][C@@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]([Li])([CH2:31]C)[CH3:30].C(Br)C=C>O1CCCC1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH2:18][CH2:31][CH:29]=[CH2:30])=[C:16]2[C:11]([CH2:12][CH2:13][C@@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of (2S)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methyl-chroman-7-yl]-carbamic acid tert-butyl ester (0.41 g, 1.0 mmole) in anhydrous tetrahydrofuran (20 mL) containing 0.010 g of 1,10-phenanthroline at −40° C. was slowly added 2.4 equivalents of 1.3 M s-butyl lithium. After 1 equivalent of s-butyl lithium had been added, the deep red color of the indicator became apparent. The reaction was allowed to stand for 1.5 hours after which allyl bromide (0.24 g, 2.0 mmole) was added. After an additional 4 hours the reaction was quenched with water (4 mL). The reaction mixture was diluted with ether (250 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and the solvent removed under vacuum. Column chromatography on silica gel (5% ethyl acetate/hexane) afforded 0.38 g (85%) of the title compound as an oil, [M+H]+: 448, [α]25D=+34.0° (c=1.03, THF).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>C(O)C.CN(C)C=O>[C:12]([O:15][CH2:16][C:17]1[NH:11][C:9](=[O:10])[C:3]2[C:2](=[N:7][C:6]([OH:8])=[CH:5][N:4]=2)[N:1]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ncc(O)nc1N
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2nc(O)cnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 5.0 g (0.0324 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide, 29.5 g (0.134 mole) of triethyl orthoacetoxyacetate and 9.5 ml of acetic anhydride. Refluxing time: 1 hour 45 minutes. Yld: 3.8 g (50%), m.p. >300° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]([C:24]3[O:25][C:26](=[O:46])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][N:37]([C:40]([CH:42]5[CH2:45][NH:44][CH2:43]5)=[O:41])[CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[C:6]=12.[CH3:47]CN(C(C)C)C(C)C.C=O.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.[Na].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)=O.O.CC#N>[CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]([C:24]3[O:25][C:26](=[O:46])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][N:37]([C:40]([CH:42]5[CH2:43][N:44]([CH3:47])[CH2:45]5)=[O:41])[CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=3)[C:6]=12
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CNC2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CN(C)C2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1-(azetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate (Example 150, 71.0 mg, 0.113 mmol), DIPEA (0.020 ml, 0.113 mmol), paraformaldehyde (69.3 mg, 2.30 mmol) and a spatula of Na2SO4 in DCM (2 ml) was stirred for 10 min at rt. Acetic acid (0.033 ml, 0.589 mmol) was then added followed by sodium triacetoxyhydroborate (82.2 mg, 0.387 mmol). After 6 hrs stirring at rt, volatiles were removed under reduced pressure. The residue was dissolved in DCM/EtOH 95:5 (10 ml) and washed with saturated sodium bicarbonate, then filtered on a phase separator and concentrated under reduced pressure. The residue was dissolved in DCM/MeOH 10:1 (1 ml), then formaldehyde (0.016 ml, 0.170 mmol) and AcOH (0.014 ml, 0.250 mmol) were added. After 5 min stirring, NaBH(OAc)3 (25 mg, 0.118 mmol) was added. The resulting mixture was stirred for 30 min at rt, then it was concentrated under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 12 g C18 column, gradient elution from 100:0 to 60:40 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded title compound (59.8 mg, 0.093 mmol, 82% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH2:1]([O:3][C:4](=[O:25])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(F)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(-c3ccc(F)cc3)cc2)cs1
Yield: 43 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromobenzyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid ethyl ester (0.9 g) synthesized in Example 155-2 and 4-fluorophenylboric acid (425 mg) were dissolved in dioxane (10 mL) and aqueous sodium carbonate solution (2 mol/L, 5 mL), tetrakis(triphenylphosphine)palladium (117 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (400 mg) as a colorless oil.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:24]=[C:23]2[C:12]([CH2:13][C:14]3[CH:18]=[CH:17][N:16]([CH2:19][C@H:20](O)[CH3:21])[C:15]=32)=[CH:11][CH:10]=1)[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C)C=O.O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:16]1[CH:17]=[CH:18][C:14]2[CH2:13][C:12]3[C:23]([C:15]1=2)=[CH:24][C:9]([O:8][CH2:6][CH3:7])=[CH:10][CH:11]=3)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2
Yield: 83.9 %

Procedure:
0.59 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.03 g of (R)-1-(7-ethoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.1 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 30 ml of anhydrous dimethylformamide, treated with 0.6 g of sodium azide and the reaction mixture was heated to 60° for 20 hours while stirring. After cooling, the solution was poured into 100 ml of water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/hexane 1:10). 948 mg (72%) of (S)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a light yellowish oil.
Reaction SMILES: [C:1]([N@@:20]1[CH2:22][CH:21]1[C:23]([O:25][CH3:26])=[O:24])(C1C=CC=CC=1)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.C(O)(C(F)(F)F)=[O:28].CCN(CC)CC.C(Cl)(C)=O>CO.C(Cl)(Cl)Cl>[C:1]([N@@:20]1[CH2:22][CH:21]1[C:23]([O:25][CH3:26])=[O:24])(=[O:28])[CH3:2]
Reactant: COC(=O)C1C[N@]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CN1C(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
(P. Davoli et al., Tetrahedron: Asym. 1995, 6, 2011-2016). (R)-Methyl 1-tritylaziridine-2-carboxylate (9.00 g, 26.24 mmol) was dissolved in MeOH/CHCl3 (1:1, 90 mL) and cooled to 0° C. under Ar and TFA (15.15 mL, 196.80 mmol) was added dropwise. After the reaction mixture was allowed to stir at 0° C. (2 h), the solvent was evaporated in vacuo. The product was dissolved in CH2Cl2 (120 mL), cooled to 0° C., and Et3N (18.29 mL, 131.20 mmol) and AcCl (2.04 mL, 28.86 mmol) were added in two portions over 5 min. The solution was stirred at 0° C. (1 h) and then washed with saturated aqueous NaHCO3 (100 mL) and saturated aqueous brine (100 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and then the crude product was purified by column chromatography (SiO2; 1/1 EtOAc/hexanes) and crystallized (cold hexanes) to yield 2.46 g (66%) of desired product as a clear crystal: mp 39-40° C.; [α]25D +84.3° (c 1.2, CHCl3); Rf=0.30 (1/2 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.16 (s, CH3C(O)), 2.51 (dd, J=1.8, 5.5 Hz, NCHH′CH), 2.58 (dd, J=1.8, 3.0 Hz, NCHH′CH), 3.16 (dd, J=3.0, 5.5 Hz, CHH′CHN), 3.80 (s, OCH3); 13C NMR (CDCl3) δ 23.7 (CH3C(O)), 30.9 (NCH2CH), 34.4 (CH2CHN), 52.9 (OCH3), 168.9 (C(O)O), 180.6 (C(O)N); HRMS (ESI) 166.0474 [M+Na+] (calcd. for C6H9NO3Na 166.0480).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([N+]([O-])=O)=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1CCC[CH2:23]1>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:22][CH:23]=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cccc(OCCOCc2ccccc2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(COCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 120 °C
Yield: 22 %

Procedure:
5 (2-Benzyloxy-ethoxy)-2-nitro-toluene (12.4 g, 43.0 mmol), N-N-dimethylformamide dimethyl acetal (6.55 g, 51.6 mmol) and pyrrolidine (3.68 g, 51.6 mmol) were dissolved in N-N-dimethylformamide (25 mL). The mixture was heated to 120° C. for 16 h. The solvent was evaporated under vacuum and the crude reaction was dissolved in 70% ethyl acetate/methanol (250 mL). The reaction was placed in a Parr Hydrogenator under a hydrogen atmosphere for 16 h with 10% palladium on carbon [10% w/w] (3.00 g) at 50 psi. The reaction was filtrated over celite and the crude mixture was purified via column chromatography with silica gel eluting with hexane/ethyl acetate to give the title compound (22% yield). 1H NMR (CDCl3) δ 7.27-7.41 (m, 6H), 7.19 (t, 1H, J=2.5 Hz), 7.13 (d, 1H, J=2.3 Hz), 6.91 (dd, 1H, J=2.5, 8.8 Hz), 6.48 (m, 1H), 4.67 (s, 2H), 4.21 (m, 2H), 3.87 (m, 2H).
Reaction SMILES: CI.[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[OH:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[O:26][CH3:32])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c(OC)c1
Reaction time: 3 h

Procedure:
Methyl iodide (2.7 g) was added to a stirred suspension of ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]-3-hydroxybenzoate (6 g) and potassium carbonate (2.6 g) in N,N-dimethylformamide (50 mL) and stirring was continued for 3 hours. The reaction mixture was poured into water (200 mL) and this was extracted three times with diethyl ether (50 mL each time). The combined diethyl ether extracts were washed three times with water (50 mL each time) and dried (MgSO4). The residue obtained on evaporation of the solvent was triturated with petroleum-ether (bp 60-80° C.) to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]-3-methoxybenzoate, yield 5.3 g, mp 78° C.
Reaction SMILES: [OH:1]O.[F:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:17])[C:8]=2[CH:7]=[CH:6][C:5]=1B(O)O.O>COC(C)(C)C>[F:3][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:17])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: OB(O)c1ccc2c(c1F)Cc1c(F)cccc1-2
Reactant: OO
Solvent: O
Solvent: COC(C)(C)C
Product: Oc1ccc2c(c1F)Cc1c(F)cccc1-2
Reaction time: 4 h

Procedure:
40 ml of hydrogen peroxide (35 percent) is added dropwise at room temperature to a suspension of 54 mmol of 1,8-difluorofluorene-2-boronic acid in 120 ml of tert-butyl methyl ether and the mixture is subsequently heated to boiling for 4 h. After cooling, the mixture is admixed with 150 ml of water, the phases are separated and the organic phase is washed twice each with water and saturated sodium sulfite solution and also with saturated sodium chloride solution, so that no more peroxide can be detected. The organic phase is dried over sodium sulfate and the solvent is removed on a rotary evaporator. Recrystallization from heptane provides 1,8-difluorofluoren-2-ol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17])[CH3:9])=[CH:4][CH:3]=1.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][CH2:13][C:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:19][C:27]2=[O:29])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(O)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CC1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 7-((1S)-1-(4-bromophenyl)ethylamino)-2-methyl-4-phenylhept-1-en-4-ol (2.2 g, 5.5 mmol) in CH2Cl2 (50 mL) was added triphosgene (3.2 g, 11 mmol) and Et3N (1.7 g, 16.5 mmol) at 0° C. The mixture was stirred at room temperature overnight, and put at room temperature for 3 days, the volatile was evaporated. The resulting mixture was washed with 1 N aq HCl and extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated to give the crude final product, which was purified by chromatography to afford two isomers.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[CH:36]([S:39](Cl)(=[O:41])=[O:40])([CH3:38])[CH3:37]>>[CH:22]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([S:39]([CH:36]([CH3:38])[CH3:37])(=[O:41])=[O:40])[CH2:2]5)[CH:26]=[CH:25][C:8]=4[C:9]=3[N:10]=2)=[N:21][CH:20]=[N:19]1)([CH3:24])[CH3:23]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)C(C)C)C3)ccc1-2

Procedure:
Following the procedure for 395, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene free base 235, diisopropylethylamine and isopropylsulfonyl chloride were reacted. The reaction mixture was loaded directly onto a silica column with no aqueous work-up to give 321 isolated as a solid (57 mg, 25%). LCMS: RT=12.20 min, [M+H]+=474. 1H NMR δ (ppm) (CDCl3): 8.39 (1 H, d, J=8.20 Hz), 7.93 (1 H, s), 7.21 (1 H, dd, J=8.21, 1.89 Hz), 7.06 (1 H, d, J=1.84 Hz), 5.96-5.88 (1 H, m), 4.42 (2 H, t, J=5.00 Hz), 4.29 (2 H, t, J=8.23 Hz), 4.15 (2 H, t, J=7.30 Hz), 3.84-3.78 (1 H, m), 3.43 (2 H, t, J=5.03 Hz), 3.16 (1 H, t, J=6.84 Hz), 1.64 (6 H, d, J=6.62 Hz), 1.40 (6 H, d, J=6.84 Hz)
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[CH3:20][NH2:21].CO>C(Cl)(Cl)Cl>[CH3:20][NH:21][C:4]([C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[C:1]([NH:5][CH2:6][S:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)=[O:19])=[O:14]
Reactant: CN
Reactant: O=C1c2ccccc2C(=O)N1CSc1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccccc1C(=O)NCSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a solution of 6.76 g (25.0 mmol) of 4-phthalimidomethylthiopyridine in 100 ml of chloroform, 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. Additional 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethanol/ethyl acetate=1:10), and the resulting crude product-was crystallized from methylene chloride-diethyl ether to give 2.645 g of the desired compound (35.1% yield, yellow crystals), mp. 118°-121° C.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[N:20]=[C:19]([C:21]([O:23]C)=O)[C:18](=[O:25])[N:17]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[C:16]=3[CH3:36])=[CH:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1)#[N:3]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[N:20]=[C:19]([C:21]([NH2:1])=[O:23])[C:18](=[O:25])[N:17]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)[C:16]=3[CH3:36])=[CH:13][CH:12]=[N:11]2)=[CH:8][CH:9]=1)#[N:3]
Reactant: COC(=O)c1nc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: N
Solvent: CO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)nc(C(N)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 87 %

Procedure:
Ammonia solution (1.12 L, 7M in MeOH, 10 eq) was added to methyl 6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (377 g) and MeOH (3.8 L, 10 vols) under nitrogen. The suspension was stirred at ambient temperature for 36 h. The mixture was then filtered, washed with MeOH (2×754 ml) and dried under vacuum. The crude material was dissolved in acetone (10.7 L) at 45° C., and filtered to remove particulates. The filtrate was is concentrated to a volume of about 3.8 L. The resulting slurry was diluted by the addition of methyl isobutyl ketone (10 L), and a further 3.2 L of solvent were removed by distillation. Further methyl isobutyl ketone (7.8 L) was added to achieve a total of about 53 relative volumes (with respect to substrate). The resulting slurry was heated to 53-60° C. and held within this temperature range until in-processes testing (DSC) showed that the desired polymorph had been achieved (62 hours for this particular batch). The slurry was cooled to 25° C. over 4 hours, and then held at 20-25° C. for 36 hours. The product was collected by filtration, and the cake washed with methyl isobutyl ketone (1.9 L). The cake was dried in a vacuum oven at 55° C. until constant weight was achieved. After drying, the title compound (310.8 g, 87%) was obtained as a pale yellow crystalline solid.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:23]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=[CH:11]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reaction time: 1 h

Procedure:
To a solution of 10 g of adenosine in 400 ml of dimethyl formamide was added 2.25 g of 60% sodium hydride (oil). After one hour, 8.5 ml of 1-bromononane was added. The reaction was stirred for 16 hours. Ice was added and the solution evaporated in vacuo. Water and ethyl acetate were added. The organic phase was separated, dried, and evaporated in vacuo to give a white solid, which was recrystallized from ethanol to yield 4.8 g of the title compound, m.p. 143-144° C. analysis for: C19H31N5O4. Calculated: C, 57.99; H, 7.94; N, 1779. Found: C, 58.13; H, 7.93; N, 17.83.