Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][O:11][CH2:32][C:31]1[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:29]([C:28]([F:27])([F:41])[F:42])[CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled solution (0° C.) of (S)-2-t-butoxycarbonylamino-3,3-diphenylpropan-1-ol (2.04 g, 6.2 mmol, Example 1 g) in tetrahydrofuran (50 ml) and dimethylformamide (10 ml) was added sodium hydride (0.187 g, 80% suspension in oil) over 15 minutes. After an additional 10 minutes 3,5-bis(trifluoromethyl)benzyl bromide (1.14 ml) was added and the solution stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue partitioned between CH2Cl2 and water. After washing the organic phase with saturated brine and drying (MgSO4), the solvent was removed in vacuo and the residue chromatographed on silica gel in ethyl acetate/hexane (0:100 to 50:50) to give (S)-2-t-butoxycarbonylamino-1-((3.5bis(trifluoromethyl)phenyl)methyloxy)3,3-diphenylpropane, 2.92 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=2[F:68])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:65])[F:66])[CH:61]=[CH:60][C:59]=2[F:68])[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:69][CH:70]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(C(F)(F)F)ccc2F)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cc(C(F)(F)F)ccc2F)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.8 %

Procedure:
To a solution of 100 mg (0.47 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 10 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 184 mg (0.47 mmol) of (4-tert-butyl-benzyl)-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amine were added. After stirring for 22 h at rt, the reaction mixture was diluted with 10 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (8 g silica gel; EtOAc/heptane 1:3; then again 8 g silicagel and DCM/heptane 70:30 to 90:10) to give 77 mg white solid (30%). MS(ISP) 548.2 (M+H)+.
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[F:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=2[F:20])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: Fc1c(Cl)cccc1N=C=S
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2F)c1O
Yield: 66.5 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (500 mg, 2 mmol) and 2-fluoro-3-chlorophenylisothiocyanate (374 mg, 2 mmol) were coupled to form the desired thiourea (583 mg, 67%). EI-MS m/z 438.2(M+).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:20][C:19](=[O:21])[O:18][C@H:17](/[C:22](/[CH3:35])=[CH:23]/[CH2:24][O:25]CC2C=CC(OC)=CC=2)[C@@H:16]([CH3:36])[CH:15]=[CH:14][C@@H:13]2[O:37][C@H:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:39][C@:12]2([CH3:46])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[Si:1]([O:8][CH:9]1[CH2:20][C:19](=[O:21])[O:18][C@H:17](/[C:22](/[CH3:35])=[CH:23]/[CH2:24][OH:25])[C@@H:16]([CH3:36])[CH:15]=[CH:14][C@@H:13]2[O:37][C@H:38]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[O:39][C@:12]2([CH3:46])[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC/C=C(\C)[C@H]2OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]3(C)O[C@@H](c4ccccc4)O[C@H]3C=C[C@@H]2C)cc1
Agent: C/C(=C\CO)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: COc1ccc(COC/C=C(\C)[C@H]2OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]3(C)O[C@@H](c4ccccc4)O[C@H]3/C=C/[C@@H]2C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: C/C(=C\CO)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Reaction time: 3 h

Procedure:
(2S,3aS,4E,6S,7S,13aR)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1E)-3-[(4-methoxybenzyl)oxy]-1-methylprop-1-en-1-yl}-6,13a-dimethyl-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxolo[4,5-f]oxacyclododecin-9-one (710 mg, 1.09 mmol) was dissolved in dichloromethane (14.0 ml) and a phosphate buffer (pH=7, 1.40 ml). 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (297 mg, 1.31 mmol) was added to the reaction solution at 0° C. and stirred for three hours. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (74.3 mg, 0.33 mmol) was added and the reaction solution was stirred at 0° C. for one and a half hour. After 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (74.3 mg, 0.33 mmol) was added and the reaction solution was stirred at 0° C. for further 30 minutes, the reaction solution was filtered with silica gel (Fuji Silysia, commercial name Chromatorex, NH, 200-350 mesh). The filtrate was washed with a saturated sodium hydrogen carbonate aqueous solution, distilled water and brine sequentially and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=4:1→3:1) to obtain the title compound (460 mg) as a colorless needle.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=3[O:24]C)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[OH:24])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)c(O)c1
Yield: 78.4 %

Procedure:
Prepared according to Method D step C from 1-cyclopentyl-3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.225 g, 0.6 mmol), boron tribromide (0.5 mL, 5 mmol) and 1.0 mL of cyclohexene to give the product (0.147 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]4[CH:13]=[CH:14][C:15]([F:19])=[CH:16][C:17]=4[CH:18]=[C:5]3[C:4]=2[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:15]1[CH:14]=[CH:13][C:12]2[N:6]3[CH2:7][CH2:8][C:9]4[CH:10]=[CH:11][C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=6[CH:36]=5)=[N:3][C:4]=4[C:5]3=[CH:18][C:17]=2[CH:16]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1ccc2c(c1)cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5cc(F)ccc5n3CC4)cc12
Temperature: 100 °C
Yield: 61.2 %

Procedure:
To a degassed solution of 2-chloro-10-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (80 mg, 0.16 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (10 mg), X-Phos (10 mg) and K3PO4 (100 mg, 0.38 mmol) were added under N2. After heated to 100° C. for 1 hour, the reaction mixture was cooled to RT, filtered and washed with EtOAc. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the residue was purified by prep-HPLC to give the product (60 mg, yield: 61.5%). 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.92˜7.98 (m, 2H), 7.65˜7.67 (m, 2H), 7.43 (d, J=7.6 Hz, 1H), 7.28˜7.32 (m, 2H), 7.15˜7.24 (m, 3H), 6.98˜7.03 (m, 1H), 6.05 (br s, 1H), 4.31 (t, J=6.4 Hz, 2H), 3.36 (s, 3H), 3.30 (t, J=6.4 Hz, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.68 (s, 3H). MS (M+H)+: 613.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:44])[CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)[C:13]2=[O:45])=[CH:4][CH:3]=1.[Si:46](Cl)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.N1C=CN=C1>>[Si:46]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:44])[CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:25]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)[C:13]2=[O:45])=[CH:4][CH:3]=1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N[C@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](Oc1ccc2cccc(N3CC[C@H](NC(=O)Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)C3=O)c2c1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-N-[1-(7-hydroxynaphthalen-1-yl)-2-oxopyrrolidin-3-yl]-2-[1-(triphenylmethyl)-1H-imidazol-4-yl]acetamide, as described above in Step C, (6.50 g, 11.0 mmol), tert-butyldiphenylsilyl chloride (4.55 g, 16.6 mol), and imidazole (1.87 g, 27.5 mol) in dry, degassed DMF (100 mL) was stirred, under argon, at 50° C. for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (125 mL). The aqueous layer was extracted further with CH2Cl2 (125 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—1% MeOH—0.1% NH4OH to yield the desired product as a pale solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10].[CH:19](=[O:21])[CH3:20]>O1CCCC1>[OH:21][CH:19]([CH:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:9](=[O:10])[O:11]1)[CH3:20]
Reactant: CC=O
Reactant: O=C1OCc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1OC(=O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A dry tetrahydrofuran solution (100 mL) of lithium diisopropyl amide (26.9 mmol) was cooled to −78 degree in a current of nitrogen, and a tetrahydrofuran solution (100 mL) of phthalide (3.0 g, 22.4 mmol) was dripped in. After stirring at −78° C. for 30 minutes, acetaldehyde (1.19 g, 26.9 mmol) was slowly added and stirred at −50° C. for 4 hours. After the temperature had risen to room temperature, distilled water was added and the mixture extracted with ethyl acetate. The organic phase was washed with distilled water and saturated brine, and dried with anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/6), and the target compound (1.96 g, 49%) was obtained as a yellow oily residue.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.N1CCCCC1>C(O)C>[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:29][CH:28]=1
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1cc[n+](CCO)cc1
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: CCO
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCO)cc3)ccc21
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution mixture of 3a (0.13 g, 0.75 mmol), 9 (0.27 g, 0.9 mmol) and piperidine (0.1 mL) in ethanol (30 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed by rotary evaporation. The residue was purified by recrystallization from methanol affording SPOH (0.18 g) as pale red solid in 53% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=6.8 Hz, 2H), 8.55 (s, 1H), 8.19 (m, 4H), 7.84 (d, J=8 Hz, 1H), 7.65 (m, 2H), 7.49 (m, 2H), 7.25 (t, J=7.2 Hz, 1H), 5.66 (s, 1H), 4.57 (m, 4H), 3.79 (m, 4H), 3.43 (m, 2H), 3.27 (m, 2H), 3.08 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.4, 144.4, 142.4, 141.7, 140.8, 126.4, 126.3, 126.2, 122.7, 122.6, 122.1, 121.1, 120.3, 120.0, 119.7, 110.4, 110.2, 71.2, 69.8, 68.8, 61.6, 600.1, 58.1, 42.8. HRMS (MALDI-TOF) m/z Calcd for C26H29N2O3 417.2172. Found 417.2184 [M+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[O:18].BrN1C(=O)CCC1=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(Cl)Cl>ClC(Cl)C.CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH2:19][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]2=[O:18]
Reactant: CCOC(=O)c1cn(C)c2c(Cl)nc(C)cc2c1=O
Reactant: C1COCCN1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(Cl)nc(CN3CCOCC3)cc2c1=O
Reaction time: 0.42 h
Yield: 39.6 %

Procedure:
Ethyl 8-chloro-1,6-dimethyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxylate (Preparation 44, 0.62 g) and N-bromosuccinimide (0.45 g) are dissolved in dichloro-ethane (100 mL). The solution is subjected to light by shining a 650W sunlamp with stirring for 25 minutes. Solvent is evaporated and the crude solid obtained is dissolved in DMF (15 mL). Morpholine (0.86 g) is added and the mixture stirred for 18 hours. The mixture is poured into CH2Cl2 (200 mL) and then washed with water (3×200 mL). The organics are dried with Na2SO4, filtered and the solvent evaporated. The crude solid is chromatographed with MeOH/CH2Cl2 (0-5%) to obtain 0.32 g (40%) of the title compound as a light orange solid. Physical characteristics: MS (ESI+) m/z 366 (M+H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:2]2.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[OH-].[Na+].Cl>CO.O.CC(C)=O>[ClH:17].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc(Cl)c1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc(Cl)c1
Yield: 87.1 %

Procedure:
In 60 ml of methanol was dissolved 23 g of N-(3-quinuclidinyl)-3-chlorobenzamide followed by addition of a solution of D-(-)-tartaric acid (13 g) in 40 ml of methanol. The mixture was ice-cooled and the resulting crystals were recovered by filtration. To the crystals was added 350 ml of methanol and the mixture was refluxed for a while. After cooling, the crystals were collected by filtration. The above operation was repeated twice and the crystals obtained were dissolved in water and sodium hydroxide solution was added. This mixture was extracted with chloroform and the extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then evaporated off to obtain a colorless oil. This oil was treated with ethanolic hydrochloric acid in acetone and the precipitated hydrochloride was recovered by filtration to give 11.4 g of the desired compound as white crystals. m.p. 244°-246° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([F:17])[C:14]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:19])=[C:13]([F:31])[CH:12]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:12]=[C:13]([F:31])[C:14]=1[C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:19]
Reactant: OB(O)c1cncnc1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1c(F)cc(-c2cncnc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure WW starting from 5-pyrimidine boronic acid and (4-bromo-2,6-difluoro-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone to give 8 mg (8%). MS (ES+) 373 m/z
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH:10]([N:16]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:14])([F:15])[CH:10]([NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)C(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(F)C(N)C1
Reaction time: 3 h

Procedure:
To a solution of 3-azido-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester (0.68 mmol, 0.18 g) in MeOH (4.0 mL), was added Pd—C (10% by wt, 30 mg) and stirred under H2 atmosphere (balloon) for 3 h. The catalyst was filtered and washed with DCM, and the filtrate was concentrated under reduced pressure to provide 3-amino-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22](=[O:33])[NH:23][C:24]2[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[O:26][N:25]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[C:29]([C:27]1[O:26][N:25]=[C:24]([NH:23][C:22]([C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[O:33])[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCCC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCNCC2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[(S)-2-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-piperidine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (655 mg; 1.413 mmol) in dichloromethane (100 mL) is added 4N hydrochloric acid in dioxane (1.25 mL; 5 mmol) and the reaction mixture is stirred at room temperature for 3 hours. More 4N hydrochloric acid in dioxane (1.25 mL; 5 mmol) is added and the stirring is continued for another 3 hours. After this time, the reaction mixture is concentrated to afford the product. The product is taken up in the mixture of ethyl acetate and saturated NaHCO3 aqueous solution to free base the product. The aqueous layer is extracted with ethyl acetate twice. The combined organics are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound, m/z 364 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH4+:16].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH2:16])=[O:7])[CH2:3]1
Reactant: CC1(C)CC(C(=O)O)C1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)CC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
Treat a solution of 3,3-dimethylcyclobutylcarboxylic acid (0.500 g, 3.90 mmol) and oxalyl chloride (0.512 mL, 5.85 mmol) in DCM (30 mL) with catalytic DMF (1 drop), stir at RT for 4 h, concentrate to dryness, add additional DCM and concentrate to dryness again. Dissolve the residue in THF (10 mL), add drop-wise to a solution of NH4OH (2 mL, 51.4 mmol) in THF (20 mL), and stir at RT overnight. Extract with EtOAc (2×), wash the combined organics with brine, dry over MgSO4 and concentrate to dryness to afford the title compound (440 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.07 (s, 1H); 6.63 (s, 1H); 2.86 (m, 1H); 1.85 (m, 2H); 1.74 (m, 2H); 1.10 (s, 3H); 1.00 (s, 3H); MS(ESI) m/z: 128.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:28][CH:29]2[CH2:33][CH:32]=[CH:31][CH2:30]2)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:29]1([CH2:28][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])[CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CCCC2)c(=O)[nH]c1=O
Yield: 34.3 %

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.10 g, 0.40 mmol) and (cyclopent-3-en-1yl)methyl toluenesulfonate (0.12 g, 0.40 mmol) in dimethylformamide (10 ml) were heated at 90° C. for overnight in the presence of sodium bicarbonate (41 mg, 0.48 mmol). After the concentration of dimethylformamide under vacuum distillation, the desirable product was obtained as white solid (45 mg) by the separation of column chromatography.