Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH3:17]O>>[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: NC(CC(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccccc1
Reaction time: 12 h

Procedure:
Thionyl chloride (19.1 g, 162 mmol) was added dropwise to a solution, cooled to 0° C., of 3-amino-3-phenylpropionic acid (8.9 g, 54 mmol) in methanol (150 ml). The reaction mixture was then stirred for 12 h under reflux (TLC control). The solvent was removed completely and the residue was dried in vacuo. The crude product was used in the next stage without being purified further.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:39]=[CH:38][C:9]2[S:10][C:11]([CH2:13][C:14]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]4[CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:41](=[NH:46])(OCC)[CH3:42].C(N(CC)CC)C>C(O)C>[ClH:1].[ClH:1].[C:41]([N:29]1[CH2:30][CH2:31][CH2:32][C@@H:28]1[CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:14]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH2:13][C:11]2[S:10][C:9]3[CH:38]=[CH:39][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][C:8]=3[CH:12]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:25][CH:24]=1)(=[NH:46])[CH3:42]
Reactant: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)(C(=O)OCC)c1ccc(OC[C@H]2CCCN2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(C)=N)cc1
Temperature: 25 °C

Procedure:
1.0 g of ethyl 3-(5-amidinobenzo[b]thien-2-yl)-2-ethoxycarbonyl-2-[4-[((2R)-2-pyrrolidinyl)methoxy]phenyl]propionate dihydrochloride was dissolved in 20 ml of ethanol, followed by the addition of 0.42 g of ethyl acetimidate hydrochloride. 0.51 g of triethylamine was added to the thus prepared solution during stirring under ice cooling, and the resulting mixture was warmed up to room temperature and stirred for 18 hours. Thereafter, the solvent was distilled off to obtain ethyl 2-[4-[((2R)-1-acetimidoyl-2-pyrrolidinyl)methoxy]phenyl]-2-ethoxycarbonyl-3-(5-amidinobenzo[b]thien-2-yl)propionate dihydrochloride. The thus obtained ester compound was dissolved in 50 ml of 5N hydrochloric acid and refluxed under heating for 60 minutes. After distilling off the solvent, the resulting residue was subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Fractions of interest were pooled and concentrated, and the resulting residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 360 mg of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(NC(C)C)(C)C.[Li].[I:27][CH2:28]I>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.O>[I:27][CH2:28][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ICI
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCOC(=O)C1(CI)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester (12.8 g, 49.74 mmol) in 73 mL of dry THF under N2 atmosphere at 42° C. was added 24.87 mL (49.74 mmol) of 2M Lithium diisopropylamine in heptane/THF/ethylbenzene dropwise to not exceed −40° C. After one hour, 4.0 mL (49.74 mmol) of diiodomethane was added and the solution was warmed to ambient temperature overnight. The resulting solution was diluted with H2O and extracted with ethyl acetate. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 18.84 g (95%) of the desired product as a brown oil. Electrospray Mass Spec: 398.2
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:19]3[C:20]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=4[N:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23](=[O:25])[CH2:24][C:18]3=[N:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[N:11]1([CH2:14][C:15]2[N:19]3[C:20]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=4[N:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23](=[O:25])[CH2:24][C:18]3=[N:17][N:16]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nnc3n2-c2ccc(Cl)cc2N(c2ccccc2)C(=O)C3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2nnc(CN3CCNCC3)n2-c2ccc(Cl)cc2N1c1ccccc1

Procedure:
2 g. of 1-[4-(t-butoxycarbonyl)-piperazinomethyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 50 ml of trifluoroacetic acid is stirred for 2 hours. The reaction mixture is evaporated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](N)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.FC1N=C([Cl:17])C(F)=CN=1>O>[OH:8][C:5]1[N:4]=[C:3]([Cl:17])[C:2]([F:1])=[CH:7][N:6]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: Fc1ncc(F)c(Cl)n1
Solvent: O
Product: Oc1ncc(F)c(Cl)n1

Procedure:
A process has now been found for the preparation of 5-fluorocytosine, which is characterised in that 2,5-difluoro-4-chloropyrimidine is reacted with a proton acid in the presence of water to give 2-hydroxy-4-chloro-5-fluoropyrimidine, and this is reacted with ammonia to give 2-hydroxy-4-amino-5-fluoropyrimidine (=5-fluorocytosine).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.BrCC1CCCCO1.[CH3:22][C:23]1[C:27]2[CH:28]=[C:29]3[C:34]4([C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[NH:36][C:35]4=[O:43])[CH2:33][O:32][C:30]3=[CH:31][C:26]=2[O:25][N:24]=1>>[O:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:36]3[C:37]4[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:34]4([C:29]5[C:30](=[CH:31][C:26]6[O:25][N:24]=[C:23]([CH3:22])[C:27]=6[CH:28]=5)[O:32][CH2:33]4)[C:35]3=[O:43])=[CH:4][CH:5]=2)=[CH:10][CH:11]=[N:12]1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: BrCC1CCCCO1
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(-c3ccno3)cc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(4-(bromomethyl)phenyl)isoxazole (0.20 g, 0.84 mmol) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one was obtained (60%) as a colorless solid: mp 192-194° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.25 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.27-7.09 (m, 2H), 7.02-6.95 (m, 2H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 5.32 (d, J=16.2 Hz, 1H), 5.15 (d, J=9.1 Hz, 1H), 4.89 (d, J=9.1 Hz, 1H), 4.83 (d, J=16.2 Hz, 1H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 169.0, 164.0, 158.2, 155.0, 150.8, 141.9, 137.4, 130.5, 129.4, 127.8, 126.8, 123.8, 123.7, 123.1, 118.0, 109.7, 108.9, 108.0, 98.9, 81.4, 56.4, 53.5, 44.1, 9.8; MS (ES+) m/z 449.9 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2ccc(F)c(-c3ccccc3Cl)c2O1
Yield: 66.6 %

Procedure:
Treatment of ((2R)-8-(2-chlorophenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate (0.7 g, 1.56 mmol) with sodium azide (0.61 g, 9.40 mmol) in DMSO (20 mL) according to the procedure described for Example 69, Step 9 provided 0.33 g (67%) of (2R)-2-(azidomethyl)-8-(2-chlorophenyl)-7-fluorochroman as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:3][OH:4]>ClCCl.CS(C)=O>[CH3:1][C:2]([CH3:13])([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COC1CCCCO1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol (20 g, 106 mmol) an TEA (44.4 mL, 319 mmol) in dry dichloromethane (300 mL) cooled in an ice bath to 0° C.±5° C. was added a solution of sulfur trioxide pyridine complex (50.7 g, 319 mmol) in anhydrous DMSO (300 mL) in one portion. There was an exotherm to 27° C. The bath was removed and the mixture allowed to stir for 20 minutes at room temperature after which time conversion was complete by TLC. The reaction was quenched with 225 mL of saturated NaHCO3, concentrated on the rotovap to remove dichloromethane and extracted with 3×200 mL of ethyl acetate. The combined extracts were washed once with 250 mL of 10% citric acid, dried over MgSO4 and concentrated. Drying under vacuum gave 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propanal as an oil. Contains ˜40% DMSO by NMR: 1H NMR (400 MHz, CDCl3) δ 9.6 (s, 1H), 4.6 (m, 1H), 3.8 (d, 1H), 3.5 (m, 1H), 3.38 (d, 1H), 1.8-1.4 (min, 6H), 1.06 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][OH:41])=[CH:38][CH:37]=1>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:41][CH2:40][C:39]3[CH:42]=[CH:43][C:36]([Cl:35])=[CH:37][CH:38]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N=C=O)cc2)COC1(C)C
Reactant: OCc1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)OCc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 110 °C
Yield: 51.4 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-isocyanato-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (240 mg) in 1,2-dichloroethane (2 ml) in a pressure tube were added sequentially N,N-diisopropylethylamine (0.24 ml) and 4-chloro-benzyl alcohol (148 mg). The tube was capped and stirring was continued while the reaction mixture was heated at 110° C. for 18 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-{2-[4-(4-chloro-benzyloxycarbonylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (174 mg, 51%) as a colourless amorphous solid. MS (ISP): 508.2 ([{37Cl}M+NH4]+), 506.2 ([{35Cl}M+NH4]+), 491.2 ([{37Cl}M+H]+), 489.2 ([{35Cl}M+H]+), 435.2 ([{37Cl}M+H—C4H8]+), 433.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:10]=[C:11]([C:16]([Br:19])=[CH:17][N:18]=1)[C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[Br:19][C:16]1[C:11]([C:12](=[O:13])[NH2:27])=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:18][CH:17]=1
Reactant: COC(=O)c1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1Br
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 50 °C

Procedure:
A solution of methyl 2-(bis(tert-butoxycarbonyl)amino)-5-bromoisonicotinate (Intermediate 83, 100 g, 232 mmol) in 7 N ammonia in methanol (600 mL) was allowed to stir at 50° C. in a 1 L sealed tube overnight. The resulting mixture was evaporated to dryness and the crude product was directly used for the next step without further purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43]1([CH3:55])[CH:48]=[CH:47][C:46]([S:49]([N:52]=[C:53]=[O:54])(=[O:51])=[O:50])=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:53]([NH:52][S:49]([C:46]5[CH:47]=[CH:48][C:43]([CH3:55])=[CH:44][CH:45]=5)(=[O:51])=[O:50])=[O:54])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)NS(=O)(=O)c4ccc(C)cc4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 41.9 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (28 mg, 0.05 mmol) in dichloromethane (5 mL) was added triethylamine (0.1 mL) and p-tolylsulfonyl isocyanate (0.012 mL, 0.08 mmol). The resultant solution was stirred at 0° C. for 1 hour and saturated aqueous sodium bicarbonate was added. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) and recrystallization from dichloromethane-ether provided N-{[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]carbonyl}-4-methylbenzenesulfonamide (14 mg, 35%) as a yellow solid. 1H NMR (CDCl3): δ 8.03 (m, 1 H), 7.84–7.76 (m, 3 H), 7.58 (d, 2 H), 7.36–7.26 (m, 5 H), 7.01 (d, 2 H), 6.66 (m, 1 H), 6.34 (m 1 H), 6.04 (m, 2 H), 4.36 (m, 1 H), 3.91 (s, 3 H), 3.38–3.30 (m, 4 H), 2.36 (s, 3 H), 2.07 (m, 2 H), 1.82–1.54 (m, 10 H); MS m/z 669 (M+1).
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20])=[CH:17][C:16]([N+:28]([O-])=O)=[CH:15][C:13]=2[N:14]=1>C(O)C.[Pd]>[NH2:28][C:16]1[CH:17]=[C:18]([C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20])[C:12]2[S:11][C:10]([NH:9][C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:31])=[N:14][C:13]=2[CH:15]=1
Reactant: CCCN(CCC)C(=O)c1cc([N+](=O)[O-])cc2nc(Nc3c(C)cc(C)cc3C)sc12
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC)C(=O)c1cc(N)cc2nc(Nc3c(C)cc(C)cc3C)sc12
Reaction time: 4 h
Yield: 70.1 %

Procedure:
A mixture of 2-(mesitylamino)-5-nitro-N,N-dipropyl-1,3-benzothiazole-7-carboxamide (61 mg, 0.139 mmol) and 10% Pd on carbon (30 mg) in ethanol (10 ml) was hydrogenated for 4 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 40 mg of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:23][C:9]1[N:8]([CH2:7][C:5]2[S:6][C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)=[CH:3][CH:4]=2)[C:16]2[C:11]([CH:10]=1)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(Br)s1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 310D using 1-[(5-bromo-2-thienyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 314B) and [3-(trifluoromethyl)phenyl]boronic acid: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.47, (m, 4H), 7.17 (m, 1H), 6.81 (d, J=3.6 Hz, 1H), 6.65 (s, 1H), 5.49 (s, 2H), 2.56 (s, 3H); MS (ES) m/z 463 (M−1).
Reaction SMILES: [CH:1]1([CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[H][H]>O=[Pt]=O.CO>[CH:1]1([CH:7]([OH:12])[C:8]([Cl:10])([Cl:11])[Cl:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC(C1C=CCCC1)C(Cl)(Cl)Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: OC(C1CCCCC1)C(Cl)(Cl)Cl

Procedure:
Adam's catalyst (0.2 g) was added to a solution of 1-(2-cyclohexen-1-yl)-2,2,2-trichloroethanol (23 g) in methanol (220 ml) and this mixture was stirred under a slight positive pressure of hydrogen. Uptake of hydrogen was complete after 400 minutes and the solution was then filtered. The filtrate was evaporated to give 1-cyclohexyl-2,2,2-trichloroethanol of 90% purity as judged by G.L.C. An attempt to purify this material by distillation through a spinning band column gave material of only 85% purity due, presumably, to decomposition brought about by prolonged heating. This material was used without further treatment.
Reaction SMILES: [CH3:1][C:2]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:4](=[O:5])[CH:3]=1.N1C=CC=CC=1.[Br:18]Br>C(O)(=O)C>[Br:18][C:3]1[C:4](=[O:5])[C:6]([C:9]([OH:11])=[O:10])=[CH:7][NH:8][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(=O)c(C(=O)O)c[nH]1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To 6-methyl-4-(1H)-pyridone-3-carboxylic acid (prepared according to the procedure described in J. Org. Chem., 1972, 37, 1145-1148) (10.0 g, 65.4 mmol) and dry pyridine (5.2 ml) in acetic acid (200 ml) at 100° C. was added bromine (14.6 g, 91.5 mmol) in acetic acid (30 ml) dropwise over 1 hour. Heating was continued for 2 hours then cooled to room temperature. The precipitate which formed on cooling was collected by filtration, and washed with methanol to give the product as a cream coloured solid (10.62 g, 70%). 1H NMR (250 MHz, DMSO-d6) δ14.75 (1H, br s), 13.45 (1H. br s), 8.58 (1H, s), 2.53 (3H, s); MS (ES+) m/z 232/234 MH]+, 214/216 [(M-(H2O))H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[O:30][CH:31]=[CH2:32]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][C:29]([O:30][CH:31]=[CH2:32])=[O:33])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: C=COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=COC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (110 mg, 0.33 mmol) in DCM (5 ml), were added triethylamine (138 μl, 0.99 mmol) and vinyl carbonochloridate (36.2 μl, 0.40 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(vinyloxycarbonylamino)acetate (70 mg; 64% yield). The product was used in the next step without any further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH3:8].[N:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=2[OH:33])=[CH:12][CH:11]=1.O>CN(C)C=O>[N:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:20][C:19]=2[O:33][CH2:7][CH3:8])=[CH:12][CH:11]=1
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(CNC(=O)OC(C)(C)C)ccc1C(=O)Nc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
Potassium carbonate (40 mg) and ethyl bromide (56 mg) were added to a solution of N-(4- pyridyl)-4-tert-butoxycarbonylaminomethyl-2-hydroxybenzamide (100 mg) in dimethylformamide (10 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The obtained crystals were recrystallized form ethyl acetate-hexane to give 60 mg of N-(4- pyridyl)-4-tert-butoxycarbonylaminomethyl-2-ethoxybenzamide.
Reaction SMILES: I[CH3:2].[N:3]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].[Na+]>CN(C=O)C>[CH3:2][N:20]([C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[C:9]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[O:10])[S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
Iodomethane (0.040 mL, 0.643 mmol) was added to a solution of N-(2-(morpholine-4-carbonyl)-5-nitrophenyl)methanesulfonamide (108 mg, 0.321 mmol) and 60% suspension of NaH (16.5 mg, 0.413 mmol) in DMF (0.5 mL) at room temperature. After 1.5 h at room temperature, the mixture was carefully quenched with water (10 mL) and extracted with EtOAc (3×4 mL). The combined EtOAc phase was concentrated, purified by silica gel chromatography, and eluted with 10-100% EtOAc in hexanes to give a yellow oil (101.3 mg, 92% yield). LCMS: (M+H)+=344.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1H, d, J=2.26 Hz), 8.27 (1H, dd, J=8.53, 2.26 Hz), 7.71 (1H, d, J=8.53 Hz), 3.69-3.78 (2H, m), 3.47-3.61 (4H, m), 3.10-3.30 (2H, m), 3.21 (3H, s), 3.17 (3H, s).