Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>N1C=CC=CC=1>[C:17]([C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)c1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Compound 113 (250 mg, 0.80 mmol) was suspended in pyridine (1.5 mL). Decanoyl chloride (122 mg, 0.64 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (4 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (294 mg, 0.63 mmol, 98%) as a solid, mp 156-157° C.; 1H NMR (500 MHz, DMSO) δ 0.80 (3, t, J=7.0 Hz), 1.15-1.33 (21, m), 1.56 (2, t, J=7.0 Hz), 2.32 (3, t, J=7.0 Hz), 7.74 (2, d, J=8.0 Hz), 7.77 (2, d, J=8.0 Hz), 10.21 (1, s), 13.90 (1, s); 13C NMR (125 MHz, DMSO): δ 13.9, 22.1, 25.0, 28.6, 28.7, 28.8, 28.9, 29.3, 31.1, 36.0, 36.5, 118.6, 126.9, 135.7, 142.9, 167.0, 167.2, 171.9; MS (LCQ, ESI+) Calculated for C22H35N4O3S2 467.2, found 467.2 (M+H)+; HRMS (FAB+, m/z) Calculated for C22H35N4O3S2 467.2151, found 467.2131 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>C(#N)C.O>[Br:17][CH2:18][CH2:19][CH2:20][O:10][C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrCCCBr
Reactant: COc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(C)c1OCCCBr

Procedure:
The mixture of 2.50 g of 2-methoxy-6-methylphenol, 3.75 g of potassium carbonate and 18.3 ml of 1,3-dibromopropane in 50 ml of acetonitrile is stirred at reflux with stirring over 16 hours. The reaction mixture is cooled, diluted with 200 ml of water and extracted with tert-butyl methyl ether (2×200 ml). The organic phases are washed successively with water (200 ml) and brine (200 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.59 (1:1 EtOAc-heptane); Rt=5.10.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:6]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:5]=1[O:35][CH3:36])=[O:3].[OH-].[Li+]>C(OCC)(=O)C.CO.C(O)(=O)C>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:6]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:5]=1[O:35][CH3:36])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)cccc1OCC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)cccc1OCC(=O)O

Procedure:
The compound of Example 71 is saponified with lithium hydroxide using the conditions described in Example 26. Chromatography of the crude residue on silica gel using ethyl acetate/methanol/acetic acid as eluant (90:9.5:0.5) affords the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH3:8])[S:5][CH:6]=1.O.[NH2:11][C:12]([NH2:14])=[S:13]>C(OCC)C.BrBr.CCO>[NH2:14][C:12]1[S:13][CH:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: CC(=O)c1cc(Cl)cs1
Reactant: NC(N)=S
Agent: BrBr
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Nc1nc(-c2cc(Cl)cs2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a solution of 4.18 g of 4-chloro-2-acetylthiophene in 30 ml of diethylether, 1.5 ml of bromine was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the organic phase was extracted. The obtained organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain brominated compound. To a solution of the brominated compound in 30 ml of EtOH, 2.1 g of thiourea was added at room temperature, and the mixture was stirred at 80° C. overnight. The precipitate was filtered, and obtained solution was evaporated under reduced pressure. Chloroform was added and then an organic layer was washed with aqueous potassium carbonate and brine, and dried over sodium sulfate. The residue obtained by the evaporation of the solvent under reduced pressure was washed with hexane:EtOAc=1:1 to obtain 2.57 g of 2-amino-4-(4-chlorothiophen-2-yl)thiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:7](N(OC)C)=[O:8])[CH3:2].[CH2:22]([Mg]Br)[CH3:23]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7](=[O:8])[CH2:22][CH3:23])[CH:13]=[C:14]([S:16]([F:18])([F:21])([F:17])([F:19])[F:20])[CH:15]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)CC)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Ethoxy-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (O3.062; 170 mg) was dissolved in absolute THF (5 ml), and ethylmagnesium bromide (0.65 ml; 2 M in diethyl ether) was added dropwise at 0° C. while stirring. After addition, the ice bath was removed and the mixture was stirred at RT for 2 h. Then further ethylmagnesium bromide (0.1 ml) was added and the mixture was stirred once again for 2 h. While cooling, 1 N hydrochloric acid was subsequently added dropwise, followed by water and ethyl acetate. The organic phase was removed and the aqueous phase was extracted twice more with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 150 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH2:28][CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[OH:31].C(N(C(C)C)C(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[OH:31])=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCC(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(O)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), 2-amino-1-(4-chlorophenyl)ethanol hydrochloride (0.033 g, 0.16 mmol), N-ethyl-N-isopropylpropan-2-amine (0.030 ml, 0.17 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.018 g, 0.13 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.031 g, 0.16 mmol), and the reaction was stirred at ambient temperature for 16 hours. It was diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was on a Biotage SP1 system using a 25-100% EtOAc/hexanes linear gradient to yield 56 mg of the title compound (80% yield).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N+:9]([O-:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1>>[CH2:7]([C@@H:8]1[C@@H:13]2[C:12](=[O:18])[CH2:17][CH2:16][CH2:15][C@@H:14]2[O:11][N:9]1[CH3:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]([O-])=CCc1ccccc1
Reactant: O=C1C=CCCC1
Product: CN1O[C@H]2CCCC(=O)[C@H]2[C@H]1Cc1ccccc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
In a dry sealed tube under N2 were placed N-(2-phenylethylidene)methylamine N-oxide (2.0 g, 13.4 mmol) and 2-cyclohexenone (5 ml). The reagents were stirred at 100° C. for 15 hours. Unreacted 2-cyclohexenone was removed by Kugelrohr distillation to yield the crude product as a viscous brown oil (K100%). The crude product was purified by flash chromatography on silica gel (Sorbsil C60, 60A) using 60:40 v/v petroleum ether (fraction of bp 40°-60° C.):ethyl acetate as the solvent system to give the unsubstituted title compound as an orange oil (2.48 g. 75%), νmax (film) 2944, 2872, 1709, 1455, 1238 cm-1 ; δH (250 MHz, CDCl3 --Me4Si) 1.75-1.95 (4H, br m), 2.20-2.40 (2H, br m), 2.50 (3H, s), 3.70-3.80 (1H, t), 2.85-2.95 (2H, t), 3.45-3.55 (1H, br m), 4.30-4.40 (1H, br m), 7.15-7.30 (5H, br m), M/z 246 (MH+ 100%) (Found: MH+ 246.149; C15H19NO2 requires MH+ 246.1522).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>CO.O1CCCC1>[CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:32][C:33]4[NH:37][C:36]5[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=5[N:34]=4)[C:12]=3[CH3:19])[O:5][CH2:4]2)[CH2:2]1
Reactant: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(OCC2OCC3(CC3)CO2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: -19 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
The (4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)-3-methylpyridin-2-yl)methanol (520 mg, 1.96 mmol) obtained in the step (2d) was mixed with triethylamine (1.09 ml, 7.84 mmol) and tetrahydrofuran (10 ml) and the resultant mixture was cooled to −19° C. Methanesulfonyl chloride (228 μl, 2.94 mmol) was added to the mixture, which was stirred at −19° C. for 30 minutes. In the same conditions, 2-mercaptobenzimidazole (324 mg, 2.16 mmol) was added to the reaction mixture. After the reaction mixture was stirred at room temperature for 2 days, methanol and NH silica gel were added to the mixture, and the solvent was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (silica gel: 80 g, elution solvent: ethyl acetate/heptane=4/6 to 7/3→methanol/ethyl acetate=1/9) to obtain the title compound (629 mg, yield: 80.7%) as a colorless foam.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:34]2[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]2)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 60 °C
Yield: 68.1 %

Procedure:
A mixture of 5-bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 8b, 0.130 g), 1-tertbutyloxycarbonylpiperazine (0.074 g) and diisopropylethylamine (6.3 ml) in dimethylformamide (3 ml) was heated at 60° C. for 3 h. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude material was purified on a silica gel eluting with dichloromethane/ethanol (0-20% gradient) to afford the title compound as a white foam (0.112 g).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:13]([OH:21])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[Cl-].[Na+]>CC(O)(C)C.CCOC(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][N:1]2[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][C:13]([OH:21])=[O:20])[N:3]=[N:2]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: C#CCCCCC(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2cc(CCCCC(=O)O)nn2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(Azidomethyl)-4-methoxybenzene (259 mg, 1.585 mmol) was solubilised in t-BuOH (15.9 ml). Hept-6-ynoic acid (201 μl, 1.585 mmol) was added followed by water (15.9 ml) copper acetate (28.2 mg, 0.159 mmol) and sodium L-ascorbate (63 mg, 0.317 mmol). The reaction mixture was stirred at RT for 72 hrs. Sodium chloride was added and the mixture was stirred vigorously. EtOAc was added and the phases were separated. The aqueous layer was re-extracted with EtOAc and the combined organics were treated with charcoal & MgSO4 (anh), stirring for 5 minutes. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to afford the title compound;
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1.CCN(C(C)C)C(C)C.[C:41]([O:45][C:46]([N:48]([CH2:63][CH:64]1[CH2:67][N:66]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:65]1)[C:49](N1C=CC=N1)=[N:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:47])([CH3:44])([CH3:43])[CH3:42]>O1CCOCC1>[CH2:23]([O:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:31])[NH:17][C@@H:16]1[CH2:15][N:12]1[N:11]=[C:10]([CH2:9][NH:8][C:49](=[N:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[N:48]([CH2:63][CH:64]2[CH2:65][N:66]([C:68]([O:70][C:71]([CH3:72])([CH3:74])[CH3:73])=[O:69])[CH2:67]2)[C:46]([O:45][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:47])[CH:14]=[N:13]1)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N=C(N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C)n1cccn1
Reactant: NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate 2,2,2-trifluoroacetate (340 mg, 0.77 mmol) in dioxane (6 mL) was added DIPEA (0.147 mL, 0.842 mmol) and a solution of tert-butyl 3-((N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboximidamido)methyl)azetidine-1-carboxylate (367 mg, 0.765 mmol) in dioxane (1 mL). After heating to 60° C. for 12 h, the reaction mixture was concentrated in vacuo and purified via silica gel chromatography (EtOAc-heptane, 0-95%) to afford the title compound (390 mg, 69%). LCMS: Rt=0.94 min, m/z=742.5 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=O)[N:7]=1.C(O)(C)C.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[O:10])[N:7]=1
Reactant: CCOC(=O)c1csc(NC)n1
Reactant: CN(C)CCN
Solvent: CC(C)O
Product: CNc1nc(C(=O)NCCN(C)C)cs1
Temperature: 100 °C
Reaction time: 6 h
Yield: 54.8 %

Procedure:
In 3.5 g of N,N-dimethylethylenediamine, 2.5 g of 2-(N-methylamino)-4-(ethoxycarbonyl)-1,3-thiazole was dissolved, followed by stirring at 100° C. for 6 hours. The reaction mixture was poured into isopropyl alcohol and the crystals so precipitated were collected by filtration, whereby 1.68 g of the title compound was obtained. Yield: 51.5%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:37]([NH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[N:15][N:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[C:17]=3[CH:18]=[CH:19][CH:20]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 25 °C

Procedure:
A chilled (0° C.) solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide (40.0 mg, 0.111 mmol) in DMF (1 mL) was treated with 4-dimethylaminopyridine (1 mg, 0.01 mmol), DIEA (0.39 mL, 2.2 mmol) and acetic anhydride (0.062 mL, 0.66 mmol). The mixture was allowed to gradually warm to room temperature. The solution was diluted with ethyl acetate (30 mL) and washed with saturated aqueous NH4Cl (3×10 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.NC(N)=[S:13]>C(O)C>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:5][SH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=S
Reactant: Fc1c(Cl)cccc1CBr
Solvent: CCO
Product: Fc1c(Cl)cccc1CS
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 3-chloro-2-fluorobenzylbromide (5.0 g), thiourea (3.4 g) in a solvent of ethanol (200 ml) was heated under reflux for 16 hours. The mixture was evaporated to dryness and to the residue was added a solution of sodium hydroxide (30 g) in water (300 ml) and the mixture heated under reflux for 1 hour. Allowed to cool to room temperature and acidified with concentrated hydrochloric acid, the product was extracted into ether to give the subtitle compound as an oil (2.51 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[O:34])[NH:29]2>>[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1/[C:27](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:28](=[O:34])[NH:29]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2c(Br)cccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 74.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 4-bromo-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 22 (43 mg, yield 74.5%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH:31]([CH3:33])[CH3:32]>C(N)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)CI
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NC=O
Product: CC(C)COc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A suspension of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (250 mg), potassium carbonate (122 mg) and 1-iodoisobutane (163 mg) in N,Ndimethyl formamide (1 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separated solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-chlorophenyl)-4-methyl-6-(2-methylpropoxy)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (169 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[N:11]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[N:18][CH:19]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].O>C(OCC)(=O)C>[N:20]1([C:17]2[N:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[CH:9]=[N:8][N:7]([CH:4]4[CH2:3][CH2:2][N:1]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:6][CH2:5]4)[N:11]=3)=[CH:15][CH:16]=2)[CH:24]=[N:23][N:22]=[N:21]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: CC(C)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1
Reaction time: 1 h

Procedure:
To a suspension of 5-((2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (Intermediate 15) (0.300 g, 0.917 mmol) in ethyl acetate (3 mL) was added triethylamine (0.169 mL, 1.22 mmol) and isopropyl chloroformate (1.10 mL, 1M solution in toluene, 1.10 mmol). The resulting solution was stirred for 1 hour. Water was added and the solution was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate) to obtain the expected product. 1H NMR (CDCl3): δ 9.45 (1H, s), 8.28 (1H, d), 8.03 (1H, d), 7.71 (1H, s), 7.58 (1H, dd), 5.28 (2H, s), 4.95 (1H, m), 4.64 (1H, m), 4.22 (1H, m), 2.21 (2H, m), 2.14 (2H, m), 1.26 (6H, d).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(#N)C>[Br:12][C:8]1[CH:7]=[C:6]([C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH3:5])[CH2:3][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: CC(N)(CO)c1cccc(Br)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of crude (RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol (8.38 g, 36 mmol) and triethylamine (6.08 ml, 44 mmol) in acetonitrile (140 ml) was treated dropwise at −2° C. with chloro-acetyl chloride (3.25 ml, 40 mmol). After complete addition, the orange colored solution was left to warm to room temperature and stirring was continued for 2 h. For the workup, to the reaction was added silica gel (10 g) and it was evaporated at reduced pressure, thereafter, it was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 90/10 as the eluent. There were obtained 9.62 g (86% of theory) of (RS)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide as a light brown oil. MS (ISP): m/z=304.1 [M+H]+, 306.1 [M+2+H]+, 308.2 [M+4+H]+.