Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[C:4]([NH:6][C:7](=[O:26])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]C)=[O:23])[CH2:18][CH2:17]1)=[O:5].[OH-].[Li+].O.CO>C1COCC1>[Cl:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[C:4]([NH:6][C:7](=[O:26])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]1)=[O:5]
Reactant: COC(=O)C1CCN(c2ccc(Cl)cc2NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(Cl)ccc1N1CCC(C(=O)O)CC1
Reaction time: 36 h

Procedure:
The mixture consisting of 90 mg of methyl 1-{2-[3-(2-chloro-4,5-difluoro-benzoyl)ureido]-4-chlorophenyl}piperidine-4-carboxylate (Ex.15), 9.6 mg of lithium hydroxide, 3 ml of water, 3 ml of methanol and 3 ml of THF is allowed to stand at room temperature for 36 hours. The volatile fractions are removed at RT under reduced pressure and the remainder is adjusted to pH=4 using 2N hydrochloric acid. The precipitate formed is filtered off with suction and purified by column chromatography (silica gel, solvent: methylene chloride:methanol=9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCCCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
4-Methylbenzoyl chloride (1.46 g, 9.5 mmol) was added dropwise to a mixture of 6-aminohexanoic acid (1.31 g, 10 mmol) and DMAP (1.22 g, 10 mmol) in THF (100 mL) at 0° C. The mixture was warmed to room temperature and stirred overnight. THF was evaporated, and dichloromethane (100 mL) was added. The mixture was washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by chromatography on silica gel to give the title compound (1.03 g, 41.5%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2N[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+].[CH3:24][CH2:25]O>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:24]=[CH:25][C:7](=[O:9])[NH:8]2)=[CH:10][CH:11]=1
Reactant: O=c1[nH]c2ccc(O)cc2[nH]1
Reactant: CCO
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1ccc2ccc(OCCCCBr)cc2[nH]1
Yield: 25 %

Procedure:
A mixture of intermediate 38 (253 mg, 1.68 mmol), 1,4-dibromobutane (0.6 mL, 5.04 mmol) and anhydrous K2CO3 (232 mg, 1.68 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=4:1) to give 7-(4-bromobutoxy)quinolin-2(1H)-one (intermediate 48) (120 mg, 25%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:58]([CH3:60])C)[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:29]=[C:30]3[C:54](=[CH:55][CH:56]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[N:37][C:33]=2[CH:32]=[CH:31]3)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:57][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].[CH3:61][O:62]C(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:58]([O:62][CH3:61])[CH3:60])[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:29]=[C:30]3[C:54](=[CH:55][CH:56]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[N:37][C:33]=2[CH:32]=[CH:31]3)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:57][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)c4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. (ESI) m/z 830 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:29]=[N-:30]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 50 °C
Yield: 77 %

Procedure:
To a solution of 2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl methanesulfonate (2.13 kg, 4.6 mol, containing also some of the corresponding bromo-compound) in dimethylformamide (4 L) stirring in a 22 L flask was added sodium azide (380 g, 5.84 mol). The reaction was heated at 50° C. for 6 h, poured into ice/water (8 L), and extracted with 1:1 ethyl acetate:heptane (20 L). The organic layer was washed with water (5 L) and brine (5 L), and the solvents removed in vacuo to afford the desired product (1464 g, 77%) as a tan solid. LCMS for C12H8BrFN8O3Na (M+Na)+: m/z=433.0, 435.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1H), 6.75 (t, J=5.7 Hz, 1H), 3.54 (t, J=5.3 Hz, 2H), 3.45 (dd, J=11.1, 5.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].O.[Cl-].[Li+].Cl>O.C(OCC)(=O)C>[C:9]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)=CC=C(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Temperature: 80 °C
Yield: 63.4 %

Procedure:
151 Parts of 1,1-dichloro-4-methylpenta-1,3-diene, 113 parts of ethyl cyanoacetate, 200 parts of cupric acetate monohydrate, 148 parts of cupric chloride, 62.6 parts of lithium chloride monohydrate and 900 parts of ethyl acetate are stirred in an atmosphere of nitrogen. The temperature is raised to 80° C. and maintained at 80°-81° C. for 5 hours. After cooling, the reaction mixture was stirred with 1180 parts of hydrochloric acid (s.g. 1.18) and 1500 parts of water for 10 minutes. The organic layer was separated and extracted twice with 590 parts of hydrochloric acid (s.g. 1.18) in 500 parts of water. The ethyl acetate solution was diluted with 900 parts of ethyl acetate and the solution washed four times with 500 parts of water. The ethyl acetate solution is evaporated by heating to 87° C. at 20 mm Hg pressure to yield 201 parts of ethyl 1-cyano- 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate (estimated strength 82.7% equivalent to 63.4% yield).
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=1)[C:37]([OH:39])=O)=[O:33].[CH2:46]([C:48]1[CH:63]=[C:62]([C:64](=[NH:67])[NH:65]O)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]>>[CH2:46]([C:48]1[CH:63]=[C:62]([C:64]2[N:67]=[C:37]([C:36]3[CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:65]=2)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CC(C)c1cc(C=O)cc(C(=O)O)c1
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3cc(C=O)cc(C(C)C)c3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 7.8 %

Procedure:
The title compound (49 mg) was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-5-isopropyl-benzoic acid (250 mg, 1.30 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (423 mg, 1.30 mmol); LC-MS**: tR=0.90 min; [M+1]+=481.85.
Reaction SMILES: [OH:1]O.[C:3]1([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.O>[C:3]1([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1ccc2c(OCCCCSc3ccccc3)cccc2[nH]1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2c(OCCCCS(=O)c3ccccc3)cccc2[nH]1

Procedure:
0.165 ml of 30% hydrogen peroxide, dissolved in 8 ml of glacial acetic acid, were added to 0.56 gm of 5-(4-phenylmercapto-butoxy)-carbostyril. The mixture was diluted with water and extracted twice with chloroform. The chloroform extract was washed with dilute sodium carbonate solution and with water, dried over magnesium sulfate and evaporated. The residue was admixed with ethyl acetate, yielding colorless crystals with a melting point of 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.[S:29]1[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30]1.[Cl-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH3:13][C:12]([NH:11][C:10]([C:8]1[S:9][C:5]2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=[C:2]([NH:1][C:34]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[O:35])[C:6]=2[N:7]=1)=[O:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: O=C(Cl)c1ccsc1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccsc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.9 %

Procedure:
0.20 g (0.50 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 5 ml of pyridine is placed in a 50 ml round-bottomed flask under argon. A solution of 0.07 g (0.50 mmol) of thiophene-3-carbonyl chloride (prepared according to FR 2 411 188) in 2.0 ml of tetrahydrofuran is then added dropwise and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.074 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 0.14 g of an impure batch is also obtained, and is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.013 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam, along with 0.11 g of an impure batch, which is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.04 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.62 (s, 9H); 1.71 (s, 6H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 7.70 (d, J=2.0 Hz, 2H); 8.50 (t, J=2.0 Hz, 1H); 8.70 (s, 1H); 11.25 (s, 1H). LC-MS-DAD-ELSD: 510(−)=(M−H)(−); 512(+)=(M+H)(+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[OH:45][CH:36]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: NCC(O)COc1ccccc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccccc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in 76% purity by HPLC. MS(ESI+): m/z=489.
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([SH:18])=[N:15][C:14]=2[CH:19]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([S:18][CH:2]3[S:6][C:5](=[O:7])[NH:4][C:3]3=[O:8])=[N:15][C:14]=2[CH:19]=1
Reactant: O=C1NC(=O)C(Br)S1
Reactant: Sc1nc2cc(Cl)ccc2s1
Product: O=C1NC(=O)C(Sc2nc3cc(Cl)ccc3s2)S1

Procedure:
This compound was prepared from 5-bromo-thiazolidine-2,4-dione and 5-chloro-2-mercaptobenzothiazole according to the procedure described in Example 5: mp 253-255 (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+]([O-])=O)=C[CH:29]=1)=[O:26].C1(C(C)O)CC1>N1C=CC=CC=1.Cl>[CH:33]1([CH:28]([O:27][C:25](=[O:26])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:20]4[CH2:21][CH2:22][CH2:23]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=4)=[CH:4][CH:3]=2)[CH3:29])[CH2:32][CH2:31]1
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(O)ccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(O)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (909 mg, 3 mmol) in pyridine (5 mL) is added 4-nitrophenyl chloroformate (6 mmol) at room temperature and then stirred for 2 h at room temperature. To the reaction is added cyclopropyl methyl carbinol and then stirred for 8 h at 80° C. The reaction mixture is diluted with 1N HCl and then extracted with ethyl acetate. The organic layer is concentrated and the residue is dissolved in EtOAc and triturated with hexane. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (996 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:9])[S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CNc1cncc(Br)c1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CN(c1cncc(Br)c1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
To a microwave vial equipped with a stir bar and charged with 5-bromo-N-methylpyridin-3-amine (0.250 g, 1.3 mmol) in isopropanol (3 ml), was added 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.820 g, 3.3 mmol) and pyridine (0.32 ml, 4.0 mmol) into the mixture. The vial was capped and placed into a CEM Microwave for 20 minutes at 80° C., while 50 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed mostly desired product. The mixture was diluted with DCM and saturated sodium bicarbonate solution, then extracted the organic layer with DCM (3×25 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography in a gradient of 0-5% isopropanol/DCM. The fractions with desired product were combined and concentrated in vacuo. This gave N-(5-bromopyridin-3-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.300 g, 57% yield) as an off-white crystalline solid. MS (ESI pos. ion) m/z: 396 (MH+). Calc'd exact mass for C13H10BrF3N2O2S: 395. 1H NMR (400 MHz, DMSO-d6): 3.24 (s, 3H), 7.79 (s, 2H), 8.01 (s, 3H), 8.46 (s, 1H), 8.66 (s, 1H).
Reaction SMILES: [OH:1][CH:2](C(O)C)[CH:3]=[CH:4][C:5]([O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[O:17]2)[CH:9]1[O:25][CH3:26])=[O:6].I([O-])(=O)(=O)=O.[Na+]>CO.O.C(OCC)C>[CH:2]([CH:3]=[CH:4][C:5]([O:7][CH:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH:10]([C:16]2([CH3:24])[CH:18]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[O:17]2)[CH:9]1[O:25][CH3:26])=[O:6])=[O:1]
Reactant: COC1C(OC(=O)C=CC(O)C(C)O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC1C(OC(=O)C=CC=O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 6-(4,5-dihydroxy-2-hexenoyloxy)-5-methoxy-4-(2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (412 mg) in a mixture of methanol (4 ml) and water (4 ml) was added sodium periodate (215 mg) in several portions at 5° C. The mixture was stirred for half hour at the same temperature and diluted with diethyl ether (30 ml). The mixture was washed with brine, dried, and concentrated in vacuo to give a crude oil, which was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane=1/1) to yield 6-(3-formylacryloyloxy)-5-methoxy-4-(2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (251 mg) as an oil.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH3:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33])[CH3:23]>C(Cl)Cl.CO>[CH3:23][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:17](=[O:19])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:11][C:12]=2[CH3:20])=[CH:27][C:26]=1[C:32]([F:33])([F:35])[F:34])[CH3:21]
Reactant: CN(C)Cc1ccc(N)cc1C(F)(F)F
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN(C)C)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 468.2 [M+H]+; tR=2.97 min (System 1); Rf=0.37 (CH2Cl2/MeOH, 9:1+0.1% NH3aq).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CN(C)C=O.Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a stirred slurry of sodium hydride (46 g, 1 mol, 50% oil dispersion) in dimethylformamide (500 mL, distilled from calcium oxide) was slowly added a solution of diethyl acetamidomalonate (217 g, 1 mol) in dimethylformamide (1200 mL). After the initial reaction, the slurry was heated to 45° C. for 1.5 hours and then 2-chloro-5-nitropyridine (159 g, 1 mol) in DMF (800 mL) was added. The mixture became dark brown during addition of the 2-chloro-5-nitropyridine. The mixture was stirred at 45° C. overnight. After cooling, the mixture was diluted with 1000 mL hydrochloric acid (0.2 N), and then extracted with dichloromethane (3×1200 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to give a dark brown oil. The oil was dry-loaded on silica gel and chromatographed on a dry-packed silica gel column. The column was eluted with petroleum ether-ethyl acetate (8:1 and then 5:1). Fractions containing the indicated compound were combined and concentrated to give pale yellow solid. Mp 82-83° C.
Reaction SMILES: Br[C:2](F)(F)[C:3]([NH:5][CH2:6][C@H:7]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:4].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[I-].[K+].C(=O)([O-])[O-:39].[K+].[K+]>C1COCC1>[ClH:20].[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C@H:7]2[CH2:6][NH:5][C:3](=[O:4])[C:2](=[O:39])[N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:15][C:16]=1[F:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)C(F)(F)Br)C1
Reactant: C1CCNC1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1)C(=O)N1CCCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[bromo(difluoro)acetyl]amino}methyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (176 mg), pyrrolidine (0.085 mL) and potassium iodide (11.3 mg) in THF (3.4 ml) was added potassium carbonate (282 mg), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate). The obtained residue was subjected to an operation similar to that of Example 38, step E to give the title compound (11.7 mg).