Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([OH:21])=[CH:14][C:15](=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([OH:21])=[C:14]([C:30](=[O:31])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Br:22])[CH:24]=3)[C:15](=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(OCc2ccccc2)ccc2c(O)cc(=O)oc12
Reactant: O=C=Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Product: Cc1c(OCc2ccccc2)ccc2c(O)c(C(=O)Nc3cccc(Br)c3)c(=O)oc12
Yield: 15.2 %

Procedure:
According to the procedure of example 2, 7-benzyloxy-4-hydroxy-8-methylcoumarin (0.813 g, 2.88 mmol) and 3-bromophenylisocyanate (0.39 ml, 3.12 mmol) were reacted in the presence of triethylamine (0.1 ml) to generate the title compound as an off-white solid, mp 229°-231° C., (0.211 g, 0.44 mmol, yield 15.2%). Analysis: Calculated for C24H18NO5Br: C, 601.13; H, 3.76; N, 2.92. Found: C, 60.04; H, 3.51; N, 2.89. 1H NMR (CDCl3): 7.94 (br s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.41 (m, 5H), 7.24 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 5.21 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[NH2:12][C:9]1[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[Cl:11]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(-c2ccc(Cl)cc2F)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.7 %

Procedure:
6-Amino-5-chloro-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid methyl ester (400 mg, 1.26 mmol) was dissolved in 10 mL methanol and 2 mL of 2N sodium hydroxide (4 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours and then acidified with a slight excess of 2N HCl. The resulting solution was concentrated and the precipitate that formed was filtered, washed with water, and dried yielding the title compound (170 mg, 44% yield): mp 194-196° C.: 1H NMR (DMSO-d6+ few drops of D2O): δ 7.92 (m, 1H), 7.54 (dd, 1H), 7.42 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=O)[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:7])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:30])=O>>[ClH:1].[Cl:30][C:13]1[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:6]([C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:7])[CH:9]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Product: Cl
Product: O=C(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Temperature: 40 °C
Yield: 100 %

Procedure:
A mixture of 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone (0.127 mol), described in International Patent Specification WO 97/21701, in phosphoryl chloride (125 ml) was stirred and heated at 40° C. for one night, stirred further at 70° C. for one night and evaporated till dryness, yielding (100%) of [2-chloro-4(3-chlorophenyl)-6-quinolinyl](4-chlorophenyl)-methanone hydrochloride (1:1) (intermediate 55).
Reaction SMILES: N.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[Na].C(O)(=O)C(O)=O>CCOCC.O.CCO>[CH3:11][Si:10]([CH3:13])([CH3:12])[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: COc1ccc([Si](C)(C)C)cc1
Agent: N
Agent: O=C(O)C(=O)O
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Ammonia (100 mL) was condensed at −78° C. (4-methoxyphenyl)trimethylsilane (18.0 g, 0.1 mol, 1.0 eq) in anhydrous Et2O (110 mL) was added followed by EtOH (80 mL) and sodium (23.0 g, 1.0 mol, 10.0 eq) portionwise at −33° C. Additional EtOH (50 mL) was added and ammonia was allowed to evaporated over 16 h. Then water (250 mL) was added to the residue and the mixture was extracted with Et2O (250 mL×3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in EtOH (20 mL) and H2O (20 mL) and oxalic acid (2.71 g, 0.03 mol, 0.3 eq) was then added. The resulting colorless solution was stirred at room temperature for 2 h. Water (100 mL) was then added and the mixture was extracted with Et2O (100 mL×3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=10:1) to furnish 4-(trimethylsilyl)cyclohexanone as a light yellow oil (14.0 g, 72% yield). 1H NMR (300 MHz, CDCl3) δ: 2.44-2.39 (m, 2H), 2.33-2.22 (m, 2H), 2.11-2.05 (m, 2H), 1.53-1.47 (m, 2H), 0.96-0.87 (m, 1H), 0.00 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#N)[CH:5]=[CH:6][C:7]=1[F:8].CI.[CH3:14]C(C)([O-])C.[Na+].C[N:21]([CH:23]=O)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:14])[C:23]#[N:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(C)(C#N)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(3,4-Difluorophenyl)acetonitrile (25.0 g, 163 mmol) and MeI (25.4 mL, 408 mmol) were dissolved in DMF (163 mL) and added dropwise to a suspension of sodium tert-butoxide (39.2 g, 408 mmol) in DMF at 0° C. The resulting reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to ambient temperature for 1 hour. The reaction mixture was diluted with 400 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 3 times with 200 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (26.45 g) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C:8]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]=2[CH2:6]1.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1>CN(C)C=O.O>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][O:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][C:8]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:7]=3[CH2:6]2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: Clc1ccc2c(c1)CC(OCCBr)c1ccccc1S2
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCOC2Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Temperature: 63 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A mixture of 10-(2-bromoethoxy)-2-chloro-10,11-dihydrodibenzo[b,f]thiepine (5.19 g, 14 mmol, prepared similarly as described in example 2), 4-piperidinecarboxylic acid ethyl ester (2.20 g, 14 mmol) and anhydrous potassium carbonate (4.70 g, 34 mmol) in dry N,N-dimethylformamide (25 ml) was stirred at 60-66° C. for 6 h. After standing overnight at room temperature, benzene (50 ml) and water (50 ml) were added, and the phases were separated. The organic layer was washed with water (2×50 ml), dried (K2CO3) and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel using benzene as eluent, affording 4.28 g (68%) of oily 1-(2-(2-chloro-10,11-dihydrodibenzo[b,f]thiepin-10-yloxy)-1-ethyl)-4-piperidinecarboxylic acid ethyl ester. The oil was dissolved in dry acetone (40 ml), oxalic acid dihydrate (1.76 g, 14 mmol) and ether were added, and the formed hydrogen oxalate was crystallised from a mixture of acetone and ether.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@:6]1([C:26]([OH:28])=[O:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([OH:24])=[O:23]>C(O)CCCC>[CH2:8]([O:23][C:22]([C@:8]1([F:25])[C@@H:7]2[C@H:9]1[CH2:10][C@@H:11]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C@@:6]2([NH2:5])[C:26]([OH:28])=[O:27])=[O:24])[CH2:7][CH2:6][CH2:11][CH3:10]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Solvent: CCCCCO
Solvent: O=S(Cl)Cl
Product: CCCCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Temperature: 50 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
225 μL of thionyl chloride was added to 300 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid suspended in 4 mL of pentanol at ice-cooling, and the mixture was stirred for 3 hours at 50° C. After standing to cool, the reaction solution was concentrated to about 1 mL under reduced pressure, 200 mL of hexane was added thereto, and the mixture was stirred for 12 hours. After the precipitated solids were filtered, the residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.), eluent: water to a 50% aqueous solution of acetonitrile), thereby yielding 188 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-pentyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=[CH:16]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(CC(OC)=O)C>C(OCC)(=O)C.CN(C)C=O>[N:15]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:12]([CH:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1cn(CCCN2CCNCC2)cn1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCCC(=O)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCn2ccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 630 mg, 1-[3-(1-imidazolyl)propyl]piperazine 580 mg, 1-hydroxybenztriazole 410 mg and N,N-dimethylformamide 15 ml was added dicyclohexylcarbodiimide 620 mg under ice-cooling and then stirred overnight at room temperature. Ethyl acetate 100 ml was added to the solution, the resultant unsoluble matter filtered off and the solution washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride in succession. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, ethyl acetate added to the residue, the unsoluble matter filtered off and the solution concentrated to dryness under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: 20% methanol - ethyl acetate) to give an oily product. This was dissolved in ethyl acetate 30 ml, 2N hydrogen chloride - dioxane 4 ml added and the precipitated powder filtered off to give 620 mg of 1-[3-(1-imidazolyl)propyl]-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine.4 hydrochloride.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[S:6]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:13]=[CH:14][C:7]1=2.ClC1C=CC=C(C(OO)=[O:40])C=1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[O:40]=[S:6]1[C:7]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])=[CH:11][C:8]=2[CH2:9][CH2:10]1
Reactant: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)CCS2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CS(=O)(=O)O
Product: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)CCS2=O

Procedure:
The product from Example 26 is treated with one equivalent of m-chloroperbenzoic acid to yield the title compound.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([O:37][CH3:38])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:39])[C:28]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:46](=[O:47])[C:44]2[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:28]3[C:29]([F:39])=[CH:30][C:31]([C:33]4([O:37][CH3:38])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:45]=2)[CH2:6][CH2:7]1
Reactant: COC1(c2cc(F)c(-c3nc(C(=O)O)ccc3F)c(F)c2)COC1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: COC1(c2cc(F)c(-c3nc(C(=O)Nc4cnn(C)c4[C@@H]4CC[C@@H](N)[C@@H](F)CO4)ccc3F)c(F)c2)COC1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-methoxyoxetan-3-yl)phenyl)-5-fluoropicolinic acid (see WO2012/225062) gave 203. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.31 (dd, J=8.7, 4.0 Hz, 1H), 8.19 (t, J=8.9 Hz, 1H), 7.95 (s, 1H), 7.49 (d, J=9.3 Hz, 2H), 4.96 (dd, J=8.1, 4.0 Hz, 1H), 4.81 (d, J=1.7 Hz, 4H), 4.65-4.37 (m, 1H), 3.97-3.73 (m, 2H), 3.72 (s, 3H), 3.41-3.25 (m, 2H), 3.15 (s, 3H), 3.12-2.99 (m, 1H), 2.22-2.12 (m, 1H), 1.81-1.71 (m, 1H), 1.70-1.60 (m, 1H), 1.57-1.52 (m, 3H). LCMS (ES+) m/z 550 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH2:30])[CH:25]=[CH:24]2)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[CH3:17][S:18]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH:30][C:14]([C:11]1[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=1)=[O:15])[CH:25]=[CH:24]2)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc2c(ccn2NC(=O)c2cnc(-c3cccc(F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.62 mmol) in EtOAc (10 mL) is added to a stirred solution of 5-methanesulfonyl-indole-1-ylamine (0.62 mmol) and K2CO3 (3.08 mmol) in EtOAc (10 mL) and H2O (10 mL) at 0° C., and the reaction mixture is warmed to rt and stirred overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is triturated with DCM to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (85 mg, 34%) as a solid. MS: 411 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.13 (s, 3H), 6.81 (m, H) 7.25-7.39 (m, H), 7.49-7.67 (m, 3H), 7.72-7.84 (m, H), 8.21-8.32 (m, 2H), 8.39 (d, H), 9.41 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:12][S:13]([NH2:16])(=[O:15])=[O:14].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][S:13]([CH3:12])(=[O:15])=[O:14])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
A mixture of 5,6-dichloronicotinic acid (800 mg, 4.16 mmol), methanesulfonamide (779 mg, 8.40 mmol), EDCI (1.56 g, 8.20 mmol), and DMAP (1.00 g, 8.20 mmol) in DCM (10 mL) was stirred at room temperature for 16 h. The reaction was quenched with water (5 mL) and the resulting mixture was concentrated. The residue was adjusted to pH around 5 by 1M HCl, extracted with DCM (30 mL×3), dried over Na2SO4. The organic layer was concentrated to afford 5,6-dichloro-N-(methylsulfonyl)nicotinamide (700 mg, 62% yield). LCMS (ESI) m/z: 269.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([CH3:18])([CH3:17])[C:13](OC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:21][NH2:22]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:14])[NH:21][N:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(=O)C2(C)C)cc1OC
Temperature: 25 °C

Procedure:
192 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) is dissolved in 600 ml of ethanol, 145 ml hydrazine hydrate is added and the mixture is heated under reflux for 17 h. The mixture is concentrated in vacuo, resuspended in 400 ml of ethanol and concentrated again. The solids are refluxed for 60 min in 400 ml of ethanol, cooled to RT and filtered. The product is washed with 50 ml of ethanol followed by 100 ml of diethyl ether and dried in vacuo at 50° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:6](O)=[O:7].[N:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[S:31][C:30]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:6]([NH:38][C:30]1[S:31][C:32]2[C:37]([N:29]=1)=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:7]
Reactant: Nc1nc2cccnc2s1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cccnc2s1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 119 %

Procedure:
The compound of example A78 was obtained by similar method described in example A75 using (2,4-Difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid (Preparation 2) (0.1 g, 0.27 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.042 g, 0.33 mmol), HOBt (0.044 g, 0.33 mmol), and EDCI (0.062 g, 0.33 mmol), N-methyl morpholine (0.034 g, 0.33 mmom) in DMF (10 mL) to provide the title compound (0.175 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][OH:12])[CH3:7])[CH3:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>C1COCC1.CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:12][CH2:11][CH2:10][CH:9]([O:8][CH:6]([O:5][CH2:3][CH3:4])[CH3:7])[C:13]([F:14])([F:15])[F:16])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCOC(C)OC(CCO)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OC(CCOc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of 2.4 g (0.049 mol) of 50% NaH in 50 ml of THF, is slowly added a solution of 10.6 g (0.049 mol) of 3-(1-ethoxyethoxy)-4,4,4-trifluoro-1-butanol in 15 ml of THF. When no more gas evolves, a solution of 6.5 g (0.041 mol) of 4-chloronitrobenzene in 65 ml of DMF is added. After 30 min., the reaction medium is poured on iced water. The reaction medium is extracted with ether. The organic phase is washed with water, dried over Na2SO4 and concentrated. The aimed product is obtained with a 78% yield after recrystallization from isopropanol. m.p.: 81° C.;
Reaction SMILES: [Ni:1].BrBr.[CH:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1>C(COC)OC.C(NCC)C>[CH-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[Ni+2:1]
Reactant: C1=CCC=C1
Reactant: [Ni]
Agent: BrBr
Solvent: CCNCC
Solvent: COCCOC
Product: [Ni+2]
Product: c1cc[cH-]c1
Reaction time: 1 h

Procedure:
29.4 g of nickel powder are suspended in 400 ml of dimethoxyethane and admixed while stirring with 27.3 ml of bromine. The mixture is stirred for 1 hour and the solvent is removed in an oil pump vacuum. The brown residue obtained is taken up in 400 ml of diethylamine while cooling in ice and admixed with 98 ml of freshly distilled cyclopentadiene. The suspension becomes green. After stirring for 12 hours at room temperature, residual solvent is removed in an oil pump vacuum and the product is isolated by Soxhlet extraction with 700 ml of petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13]S(C)(=O)=O)[C@H:9]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)[C@H:9]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH2:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc(F)c2)[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 90 °C
Yield: 15.3 %

Procedure:
A vial containing a mixture of (2S,3S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (106.0 mg, 0.24 mmol), 3-fluorophenol (29.3 mg, 0.26 mmol), and K2CO3 (39.5 mg) in DMF (2.5 mL) was capped and heated for 60 h at 90° C. The mixture was cooled to rt and filtered. The filtrate was concentrated and the residue was purified by FCC to afford the title compound (17 mg, 15%). MS (ESI): mass calcd. for C25H36FN3O4, 461.57; m/z found, 462.3 [M+H]+. 1H NMR (CDCl3): 7.25-7.19 (m, 1H), 6.74-6.64 (m, 2H), 6.64-6.57 (m, 1H), 5.09-4.70 (m, 2H), 3.81-3.49 (m, 6H), 2.90-2.76 (m, 1H), 2.59-2.29 (m, 5H), 2.15-1.72 (m, 7H), 1.64-1.53 (m, 2H), 1.49-1.41 (m, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](C2C=CC=CC=2)[N:3]=1.ClC1C=C(Cl)N=CN=1.[CH2:23]([CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26]O)[CH3:24]>CC(C)CCO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([CH2:26][CH:25]([CH2:23][CH3:24])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:7]=1
Reactant: CCCCC(CC)CO
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: Clc1cc(Cl)ncn1
Solvent: CC(C)CCO
Product: CCCCC(CC)Cc1cc(Cl)ncn1
Yield: 76.2 %

Procedure:
The compound is prepared analogously to the method described in Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloropyrimidine and 3-methylbutanol by 2-ethylhexanol. Yield: 76.2% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=1[NH2:12].Br[C:14]1[S:15][CH:16]=[CH:17]N=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[N:12]=[C:14]1[S:15][CH:16]=[CH:17][N:8]1[C:6]2=[O:7]
Reactant: Brc1nccs1
Reactant: COc1cccc(C(N)=O)c1N
Product: COc1cccc2c(=O)n3ccsc3nc12
Yield: 87.1 %

Procedure:
16.6 g of 3-methoxyanthranilamide and 16.4 g of 2-bromothiazole were stirred for 7 hours at 150° C. After working up in the conventional manner there was obtained 20.2 g (87%) of the above compound; m.p. 230°-232° C.