Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:62])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:24]([O:56][CH3:57])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:54][CH3:55])[C@@H:34]([CH3:53])[C:35](=[O:52])[NH:36][C@@:37]1([C:46](=[O:51])[NH:47][CH2:48][CH2:49][CH3:50])[CH2:39][C@@H:38]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:95]=[C:96]1[CH:100]=[CH:99][C:98](=[O:101])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH2:110])=[O:108]>CN(C=O)C>[O:101]=[C:98]1[CH:99]=[CH:100][C:96](=[O:95])[N:97]1[CH2:102][CH2:103][CH2:104][CH2:105][CH2:106][C:107]([NH:109][NH:110][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:62])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:24]([O:56][CH3:57])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:54][CH3:55])[C@@H:34]([CH3:53])[C:35](=[O:52])[NH:36][C@@:37]1([C:46](=[O:51])[NH:47][CH2:48][CH2:49][CH3:50])[CH2:39][C@@H:38]1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:108]
Reactant: CCCNC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C)C[C@@H]1c1ccccc1
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)[C@]1(NC(=O)[C@H](C)[C@@H](OC)[C@@H]2CCCN2C(=O)C[C@@H](OC)[C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN2C(=O)C=CC2=O)C(C)C)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.9 mg (9 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S,2R)-2-phenyl-1-(propylcarbamoyl)cyclopropyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 3 ml of DMF and then admixed with 10.4 mg (54 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 8.3 mg (54 μmol) of 1-hydroxy-1H-benzotriazole hydrate, 9 μl of N,N-diisopropylethylamine and with 9.5 mg (36 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT overnight and then concentrated under high vacuum. The remaining residue was purified by means of preparative HPLC. Thus, 4.3 mg (22% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Crude tert-butyl (S)-3-cyclopentyl-1-hydroxypropan-2-ylcarbamate from the previous step was dissolved in CH2Cl2 (30 mL). Et3N (3.2 mL, 24.3 mmol) was added and the mixture was cooled to 0° C. A solution of MsCl (1.1 g, 9.7 mmol) in CH2Cl2 (10 mL) added dropwise. After stirring for an additional 2 h, water (30 mL) was added and the mixture was extracted with CH2Cl2 (2×30 mL). The combined organic layers were washed with brine, dried over MgSO4, and evaporated to give crude tert-butyl (S)-3-cyclopentyl-1-(methanesulfonyloxy)propan-2-ylcarbamate that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHZ) δ 1.09 (m, 2 H), 1.46 (s, 9 H), 1.50 (m, 3 H), 1.60 (m, 3 H), 1.81 (m, 3 H), 3.02 (s, 3 H), 3.86 (m, 1 H), 4.17 (dd, J=10, 4 Hz, 1 H), 4.27 (dd, J=10, 3.2 Hz, 1 H), 4.59 (brs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[C:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=1.Cl[CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][NH:29][C:28]1=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH:6]=[C:5]2[C:18]1[CH2:19][CH2:20][N:21]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[CH2:22][CH:23]=1
Reactant: O=c1[nH]ccn1CCCl
Reactant: Fc1ccc(-n2cc(C3=CCNCC3)c3cc(Cl)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1CCN1CC=C(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 92.5 °C

Procedure:
5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (6.0 kg. 16.5 mol), 1-(2-chloroethyl)imidazolon (3.19 kg, 1.3 eq.), sodium carbonate (anhydrous) and methyl isobutyl ketone (60 L) were mixed. The reaction mixture was heated under N2-cover and stirring until 90-95° C., and was stirred over night at this temperature. The next day the reaction mixture was filtered while still hot. The apparatus and filter cake were washed with further 2.5 L of methyl isobutyl ketone. The combined filtrates were left over night for crystallisation. The product was isolated on a nutch, washed with 7.5 L n-Heptane and dried over night in vacuum at 60° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:13][C:10]2[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 46.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (390 mg, 1.83 mmol), 4-chloro-2-nitrobenzene-1-sulfonyl chloride (Intermediate 454) (565 mg, 2.22 mmol), DMAP(cat) and pyridine (0.3 ml, 5.55 mmol) in DCM (7 ml) gave the title compound (370 mg, 46%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:20]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-(4-hydroxy-phenyl)-2-phenyl-ethanone (10.00 g, 47.12 mmol) was dissolved in pyridine (60 mL) and methoxylamine hydrochloride (5.90 g, 70.64 mmol) was added. The resulting reaction mixture was stirred at room temperature for 14 hours, and then concentrated. The solids were washed with ether, and the ether layers were combined and concentrated to afford the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 4.06 (s, 2 H) 6.73 (d, J=8.21 Hz, 1 H) 7.18 (dt, J=15.46, 7.66 Hz, 2 H) 7.38-7.44 (m, 1H) 7.50 (d, J=7.92 Hz, 1 H) 7.81 (s, 2 H) 8.55-8.64 (m, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:17]([OH:19])=O)[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10]2)=[C:5]([O:20][CH3:21])[CH:4]=1)#[N:2].C[N:23]([CH:25]=O)C.C(Cl)(=O)C(Cl)=O.[F:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38]NC)=[CH:36][CH:35]=1>C(Cl)Cl>[F:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][CH2:25][NH:23][C:17]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[O:20][CH3:21])[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10]2)=[O:19])=[CH:36][CH:35]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C#N)ccc1C1(C(=O)O)CCc2cncn21
Reactant: CNCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C1(C(=O)NCCc2ccc(F)cc2)CCc2cncn21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Crude 5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.168 g, 0.59 mmol) is suspended in CH2Cl2 (3 mL) and cooled to 0° C. To it is added DMF (0.2 mL) followed by the addition of a CH2Cl2 solution of oxalyl chloride (0.6 mL, 2.0 M). After 2 h, 4-fluoro-N-methylbenzylamine (0.23 mL, 1.78 mmol) is added. The reaction is stirred for another 2 h, evaporated to dryness, and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase is dried (Na2SO4), filtered, and concentrated. The crude residue is purified via flash column chromatography (2-5% MeOH/CH2Cl2) to give 5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (4-fluorobenzyl)methylamide as a yellow solid. MS (ESI) m/z 405.2 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.60 (s, 3H), 2.76-2.88 (m, 2H), 2.95-3.04 (m, 1H), 3.57-3.69 (m, 1H), 3.74 (s, 3H), 4.43 (d, J=14.4 Hz, 1H), 4.58-4.70 (m, 1H), 6.79 (s, 1H), 6.86-6.94 (m, 1H), 6.96-7.05 (m, 2H), 7.10 (s, 1H), 7.19-7.25 (m, 3H), 7.55 (s, 1H). Resolution of the (R) and (S) enantiomers of the title compound is achieved by chiral HPLC using ChiralPak AD column with a 6:4 EtOH/hexane mobile phase to give enantiomer A (tr=30.2 min) and enantiomer B (tr=36.0 min).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][NH:7][C:6]=2[N:16]=1.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:23])=[CH:20][C:19]=1[O:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][NH:7][C:6]2[N:16]=[C:2]([NH:17][C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:23])=[CH:20][C:19]=3[O:34][CH3:35])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CNc2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)NCC(F)(F)C(=O)N2C
Yield: 33.5 %

Procedure:
A mixture of 0.08 g (0.32 mmole) of 2-chloro-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292), 0.093 g (0.35 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.092 g (0.48 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in pressure tube at 120 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 10:90-100:0) to gave 0.051 g of give 4-(7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-303) as a white solid.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH2:12]([N:16]=[C:17]=[S:18])[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:12]([NH:16][C:17](=[S:18])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: CCCCN=C=S
Solvent: CCO
Product: CCCCNC(=S)Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (7.5 g, 0.05 mole) and butyl isothiocyanate (5.7 g, 0.05 mole) were mixed in ethanol (120 ml) and the mixture was refluxed for 30 minutes. The resulting solution was chilled in ice and upon scratching the product crystallized out as a white solid. The mixture was filtered and the solid was washed with ether. The product was dried to give a pale tan crystalline powder. Yield 9.8 g (74%), m.p. 129°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:17].C(N(CC)CC)C.ClC(OCC)=O.[NH2:43][OH:44]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:43][OH:44])=[O:25])=[O:17]
Reactant: O=C(O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
6-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (168 mg, 41%) as a brown solid. LC-MS (m/z) 412 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2]
Reactant: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1OCC
Temperature: 65 °C
Reaction time: 20 h
Yield: 64.7 %

Procedure:
Into a solution of methyl 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (1.8 ml), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (283 mg) as light yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.C[O:23][C:24](=O)[C:25]([CH3:28])([CH3:27])[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:24](=[O:23])[C:25]([CH3:28])([CH3:27])[NH:26][C:12]2=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)N
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)NC(=O)N(c2ccc(C(C)(C)C)cc2)C1=O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a suspension of 15 g of 4-tert-butylphenyl-isocyanate in 200 mL of toluene are successively added 31.52 mL of triethylamine and 13.15 g of 2,2-dimethylglycine methyl ester hydrochloride. The reaction mixture is refluxed for 24 h, cooled to room temperature, poured into distilled water and extracted with ethyl acetate. The organic phase is washed successively with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in diethyl ether and the solid formed is filtered off and dried to give 17.75 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.C([N:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)(OC(C)(C)C)=O>>[NH:25]1[CH2:30][CH2:29][CH:28]([O:31][C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: c1ccc(OCCOc2nccnc2OC2CCNCC2)cc1
Yield: 35.5 %

Procedure:
The title compound was prepared according to the procedure described in Example 49 starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1, Step 1) and N-Boc-4-hydroxypiperidine (234 mg, 1.16 mmol) to give 112 mg (35%) of the title product. HRMS m/z calcd for C17H23N3O3 (M)+ 315.1583, found 315.1570.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][CH:14]([S:17]([NH2:20])(=[O:19])=[O:18])[CH2:15][CH3:16]>>[CH:14]([S:17]([NH:20][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[F:1])(=[O:19])=[O:18])([CH2:15][CH3:16])[CH3:13]
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C(O)c1cc(F)c(F)cc1F
Product: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Yield: 46 %

Procedure:
Prepared according to Preparation 42 using 2,4,5-trifluorobenzoic acid (0.25 g, 1.4 mmol) and butane-2-sulfonamide (0.0.29 g, 2.1 mmol) to yield the title compound (0.19 g, 45%) as a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:12]2[C:8](=[N:9][NH:10][C:11]2=[O:13])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[O:13]=[C:11]1[NH:10][N:9]=[C:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[N:12]12
Reactant: COC(=O)C1CCc2n[nH]c(=O)n21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCc2n[nH]c(=O)n21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid methyl ester (0.50 g, 2.7 mmol) was dissolved in THF (3.0 mL). LiOH (0.14 g, 3.3 mmol) was dissolved in water (3.0 mL), which was added to the THF mixture and stirred at room temperature for 30 min. The mixture was acidified with 1N HCl and extracted with DCM. The organic layers were dried over MgSO4, filtered through CELITE®, and concentrated in vacuo to give 3-Oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:21]([NH2:24])[CH:22]=[CH2:23].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:21]([NH:24][S:17]([C:13]1[S:14][C:15]([Br:16])=[C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])[CH:12]=1)(=[O:19])=[O:18])[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNS(=O)(=O)c1cc(-c2sc(NC(C)=O)nc2C)c(Br)s1

Procedure:
4-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonylchloride, prepared as in Step III of Example 23 (100 mg; 0.229 mmol; 1 eq) is dissolved in DCM (10 ml). Allyl amine (0.15 ml; 1.14 mmol; 5 eq) and DIEA (0.17 ml; 0.70 mmol; 3 eq) are added under a nitrogen atmosphere. After 2 hours reaction, solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is purified by reverse preparative HPLC, affording N-(5-{5-[(allylamino)sulfonyl]-2-bromo-3-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide as a white solid (35 mg; 35%).
Reaction SMILES: [I-:1].[Na+].CC1C=CC(S(O[CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)(=O)=O)=CC=1>CC(C)=O>[I:1][CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccccc23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCc1c[nH]c2ccccc12
Yield: 100.3 %

Procedure:
Sodium iodide (827 mg, 5.52 mmol, 2 equiv) was added to a solution of 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (909 mg, 2.76 mmol, 1 equiv) in acetone, and the mixture was refluxed for 16 h. Upon cooling the reaction, it was evaporated under reduced pressure and the residue was taken into dichloromethane. The organic layer was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.7, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as an oil (789 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 2.07-2.14 (m, 2H); 2.78 (t, 2H, J=7.6 and 6.8 Hz); 3.29 (t, 2H, J=6.8 Hz); 6.95-6.99 (m, 1H); 7.04-7.08 (m, 1H); 7.14 (d, 1H, J=2 Hz); 7.32-7.34 (m, 1H); 7.52 (d, 1H, J=8 Hz); 10.81 (s, 1H); MS for C11H12IN m/z 285.12 (M+H)+.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1I.C[O:16][B:17](OC)[O:18]C.Cl>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[B:17]([OH:18])[OH:16]
Reactant: Fc1ccc(I)c(Cl)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 2-chloro-4-fluoro-1-iodobenzene (19.6 mmol, 5.0 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-chloro-4-fluorophenyl)boronic acid as a white precipitate. The white precipitate (1.10 g, 33%) was filtered and dried. 1H NMR (CDCl3, 300 MHz): 7.96 (1H, t, J 8.1 Hz), 7.11 (1H, dd, J 8.8 and 2.5 Hz), 7.04 (1H, td, J 8.4 and 2.5 Hz), 5.28 (2H, s.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[C:6]([CH:13]=1)[CH2:7][O:8][CH2:9][C:10](O)=[O:11].[CH:34]1(N=C=NC2CCCCC2)CCCCC1.C[S:50]([NH2:53])(=[O:52])=[O:51]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[C:6]([CH:13]=1)[CH2:7][O:8][CH:9]([C:10](=[O:11])[CH3:34])[S:50]([NH2:53])(=[O:52])=[O:51]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1COCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(OCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.8 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyloxy)-acetic acid (0.11 g, 0.22 mmol) in dichloromethane (10 mL) was added 4-dimethylaminopyridine (0.04 g, 0.33 mmol) and 1,3-dicyclohexylcarbodiimide (0.049 g, 0.24 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes and then treated with methanesulfonamide (0.025 g, 0.26 mmol). The reaction was stirred at ambient temperature for 18 hours, filtered through a pad of celite and the resulting filter cake was washed with dichloromethane. The combined organics were concentrated in vacuo and purified via chromatography on silica gel to give the title compound (0.045 g, LRMS: 556.2).