Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[C:8]([CH3:27])=[CH:7][C:5]=2[N:6]=1.OS(O)(=O)=O.[CH3:33]COC(C)=O.C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:19]([O:21][CH3:33])=[O:20])[C:8]([CH3:27])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Preparation of (S)-2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid from above in MeOH (25 mL) was added H2SO4 (200 μL). The reaction mixture was stirred at rt overnight. EtOAc (20 mL) and saturated NaHCO3 solution (50 mL) were added. The layers were separated, dried, filtered, and concentrated in vacuo. The crude mixture was a mixture of the desired (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate and (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate. t-Butyl acetate was added (20 mL) and perchloric acid (500 μL). The mixture was stirred at rt for 3 hr, where all (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate was converted to (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. EtOAc (10 mL) and saturated NaHCO3 solution (50 mL) were added. The layers were separated, dried, filtered, and concentrated in vacuo. LCMS-ESI+: calc'd for C21H23ClN2O3S: 419.1 and 421.1 (M+H+); found: 419.2 and 421.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[OH:4].Cl.N1C=CC=CC=1>>[NH:8]1[CH:9]=[C:5]([C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH:30]=2)([OH:4])[CH:2]([CH3:1])[CH3:40])[N:6]=[CH:7]1
Reactant: CC(C)C(O)(c1cccc(-c2cccs2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2cccs2)c1)c1c[nH]cn1
Yield: 87.6 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-methyl-1-[3-(2-thienyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.21 g) and pyridine hydrochloride (465 mg), the title compound (585 mg) was obtained as colorless plate crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[C:7]([O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:6]=1)=[O:4].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH:12]1([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=2[O:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Yield: 92.1 %

Procedure:
A solution of 5-(cyclopropylamino)-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (400 mg, 1.53 mmol), sodium hydroxide (244 mg, 6.1 mmol) in THF/H2O 1/1 (10 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. Water was added and the pH was adjusted to 2 by addition of 1 N HCl. Extraction with ethyl acetate (30 mL) was followed by washing with brine (6×30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 50 g, 50% ethyl acetate in petroleum ether) to yield the title compound (350 mg, 92%) as yellow solid; MS (EI): m/e=249.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Reactant: NC(=NO)C1CC1
Product: Cc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 163A and 36 mg (0.36 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 60 mg (51% of theory).
Reaction SMILES: [CH:1]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Cl)[N:7]=1)([CH2:3][CH3:4])[CH3:2].[CH2:14]([O:16][C:17](=[O:30])[CH:18]([CH3:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:30])[CH:18]([CH3:29])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH:1]([CH2:3][CH3:4])[CH3:2])[N:7]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Reactant: CCC(C)Sc1cccc(CCl)n1
Product: CCOC(=O)C(C)Cc1cc(F)c(OCc2cccc(SC(C)CC)n2)c(F)c1
Yield: 90.8 %

Procedure:
2-sec-Butylsulfanyl-6-chloromethyl-pyridine (28 mg, 0.13 mmol) in Step C of Preparation Example 5 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (30 mg, 0.13 mmol) in Step B of Preparation Example 34 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 96%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.[CH2:9]([NH2:12])[CH2:10][NH2:11]>O1CCCC1.O>[N:4]1([CH2:3][CH2:2][N:11]=[CH:10][CH2:9][NH2:12])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: BrCCn1cccn1
Reactant: NCCN
Solvent: O
Solvent: C1CCOC1
Product: NCC=NCCn1cccn1
Yield: 50 %

Procedure:
A solution of 1-(2-bromoethyl)pyrazole [6d] (12 mmol) in tetrahydrofuran was added dropwise to a solution of ethylenediamine (0.24 mol) in water. The mixture was refluxed for 4 hours. The THF was removed under vacuum and the water phase was washed with dichloromethane. After drying under vacuum resulted a yellow oil which was formulated as pz(CH2)2NH(CH2)2NH2 (1). Yield: 50%
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: ClCCCCCCI
Reactant: c1csc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCCCCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a stirred solution of 2,2′-bithiophene (10.0 g, 60.24 mmol) in anhydrous THF (150 ml) was added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 1-chloro-6-iodohexane (14.55 g, 50.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. NH4Cl, and the reaction mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water, brine, and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica, eluting with petroleum ether, to give 5-(6-chlorohexyl)-2,2′-bithiophene as a white solid (7.73 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.14 (d, J=5.3 Hz, 1.3 Hz, 1H, Ar—H), 7.08 (dd, J=3.5 Hz, 1.1 Hz, 1H, Ar—H), 6.97 (m, 2H, Ar—H), 6.66 (d, J=3.5 Hz, 1H, Ar—H), 3.51 (d, J=6.6 Hz, 2H, ClCH2), 2.78 (t, J=7.1 Hz 2H, ArCH2), 1.61-1.81 (m, 4H, CH2), 1.35-1.51 (m, 4H, CH2); MS (m/e): 282 (M+, 2%), 166 (8), 123 (39), 110 (22), 97 (100).
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.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.[Cl-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[C:6]3[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:13])[S:9][C:5]=3[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nn(C(=O)OC(C)(C)C)c3sc(C(=O)NC(C)(C)c4ccccc4)nc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.7 %

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 0.09 g (0.53 mmol) of 4-methoxybenzoyl chloride (prepared according to J. Org. Chem. 1976, 41, 2566) 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). 0.05 g of tert-butyl 3-(4-methoxy-benzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 0.16 g of an impure batch is also obtained, and is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.04 g of tert-butyl 3-(4-methoxybenzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-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 1.61 (s, 9H); 1.71 (s, 6H); 3.86 (s, 3H); 7.10 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.40 (d, J=7.5 Hz, 2H); 8.07 (d, J=8.5 Hz, 2H); 8.71 (s, 1H); 11.25 (broad s, 1H). LC-MS-DAD-ELSD: 534(−)=(M−H)(−); 536(+)=(M+H)(+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[F:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([CH:9]=1)[O:10][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27]
Reactant: O=Cc1cc([N+](=O)[O-])c(O)cc1F
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1cc(F)c(C=O)cc1[N+](=O)[O-]

Procedure:
Using 2-fluoro-4-hydroxy-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a white solid: ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20]>C(#N)C>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH2:2]1
Reactant: OCC1CCCNC1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In an oven-dried 25 mL flask was placed piperidine-3-yl-methanol (1.12 g, 10 mmol) in acetonitrile (10 mL), followed by addition of potassium carbonate (1.38 g, 10 mmol) and 4-bromobutyronitrile (0.90 mL, 9 mmol). The reaction mixture was stirred at rt. for 12 h. The mixture was filtered and evaporated to dryness. Addition of H2O (20 mL) was followed by extraction with ethyl acetate (3×20 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce 1.50 g of crude 6 which was used without further purification in the synthesis of compound 7.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[NH2:19][NH2:20]>C(O)C>[F:14][C:13]([F:16])([F:15])[C:12]1[C:7]([O:6][CH2:5][C:4]([NH:19][NH2:20])=[O:3])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ncccc1C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)COc1ncccc1C(F)(F)F
Yield: 77 %

Procedure:
As described for example 112a, (3-trifluoromethyl-pyridin-2-yloxy)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 77%). MS: m/e=236.2 [M+H]+.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:68])[CH:10]([NH:25][C:26]([NH:28][CH:29]([C:56]([O:58]CC2C=CC(OC)=CC=2)=[O:57])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([Sn](CCCC)(CCCC)CCCC)[CH:42]=2)=[O:36])=[O:27])[CH2:11][CH2:12][C:13]([O:15]CC2C=CC(OC)=CC=2)=[O:14])=CC=1.C(O)(=O)C.[I-:75].[Na+].ClN1C(=O)CCC1=O>CO>[C:56]([CH:29]([NH:28][C:26](=[O:27])[NH:25][CH:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:8])=[O:68])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41]([I:75])[CH:42]=1)=[O:36])([OH:58])=[O:57]
Reactant: [I-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(=O)NCCCCC(NC(=O)NC(CCC(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)C(=O)OCc2ccc(OC)cc2)c1
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCC(NC(=O)NC(CCCCNC(=O)c1cncc(I)c1)C(=O)O)C(=O)O
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
To a solution of 7 (0.025 g, 0.023 mmol) in 2 mL methanol was added 0.020 mL acetic acid and sodium iodide (0.017 g, 0.113 mmol), followed by N-chlorosuccinimide (0.025 g, 0.187 mmol). After 20 min at room temperature, the solvent was removed under a stream of nitrogen. A solution of TFA in CH2Cl2 (1:1, 2 mL) was then added to the residue. After 1 h at room temperature, 8 (0.008 g, 62%) was isolated by HPLC (Econosphere C18 10μ., 250×10 mm, H2O/CH3CN/TFA (85/15/0.1), 4 mL/min, product peak eluting at 10 min). 1H NMR (400 MHz, D2O) δ 9.00-9.15 (m, 3H), 4.18-4.24 (m, 2H), 3.40-3.41 (m, 2H), 2.45-2.49 (m, 2H), 2.12-2.13 (m, 1H), 1.85-1.97 (m, 2H), 1.64-1.73 (m, 3H), 1.44 (m, 2H). ESI-Mass calcd for C18H24IN4O8 [M+H]+ 551.1, found 551.0. FAB-HRMS calcd for C18H24IN4O8 [M+H]+ 551.0639, found 551.0607.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:46]([C:49]1[S:50][CH:51]=[C:52]([C:54](O)=[O:55])[N:53]=1)[CH2:47][CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:54]([C:52]3[N:53]=[C:49]([CH2:46][CH2:47][CH3:48])[S:50][CH:51]=3)=[O:55])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: CCCc1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.24 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.14 g), 2-propylthiazole-4-carboxylic acid (example 87, step c) (0.084 g) and triethylamine (0.27 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.14 g.
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=N1.N1C=CC=CC=1.[C:19](OCC)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[CH3:20][C:19]1[O:21][C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nnc(-c2ccc(Br)cn2)o1
Reaction time: 3 h
Yield: 80 %

Procedure:
In 130 ml of acetic anhydride was dissolved 8.6 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6. And then the solution was added with 15 ml of pyridine and stirred for 3 hours for reaction. The reaction mixture was added with ethyl acetate and extracted to separate organic layer. And then the organic layer was washed with water and brine. The organic layer was dehydrated, filtrated and concentrated in vacuo to give 7.3 g of the title compound. Yield 80%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[CH:4][CH:3]=1.[OH-].[Na+].[BrH:16]>C(O)(=O)C>[Br:16][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Brc1ccc(-c2csc(Br)n2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84 %

Procedure:
A suspension of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.12 g, 20.0 mmol), prepared in the previous step, in 30 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 7 h. The yellow suspension was poured into 200 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 17 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(4-bromophenyl)-1,3-thiazole (5.36 g, 84%) as a light yellow solid, mp 117-119° C.; MS (ES) m/z 318/320/322 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22]([C:28]#[N:29])=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH2:30]=[O:31]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22]([C:28]#[N:29])=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:30][OH:31])[N:10]=1
Reactant: C=O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Solvent: CO
Solvent: O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Temperature: 100 °C
Yield: 92.1 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (2.0 g, 4.60 mmol) in methanol (30 mL) was treated with a solution of 37% aqueous formaldehyde (7.5 mL, 100.72 mmol). The resulting mixture was heated to 100° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and was diluted with water. The resulting precipitate was collected by filtration, was washed with water and was dried in vacuo to afford 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (1.97 g, 92%) as a light yellow solid. ES+-HRMS m/e calcd for C18H14N6O5Cl2 (M+H+) 465.0476, found 465.0475.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].CO[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1>C(Cl)Cl>[S:10]1[CH:11]=[CH:12][CH:8]=[C:9]1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccsc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cccs1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirred 300 mL CH2Cl2 solution in a −78° C. cooling bath was added chlorosulfonic acid (14.5 mL, 217.8 mmol). A solution of 3-methoxythiophene (10.0 g, 87.59 mmol) in 80 mL of CH2Cl2 was added slowly along the side wall of the flask. After 30 min, the cooling bath was removed. Reaction was continued at room temperature for 2 h. Stirring was stopped, the mixture was set still for approximately 10 min, and filtered directly and carefully through a 2-in silica gel pad. The green glue residue was extracted several times with CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to afford 10.75 g (58%) of thiophene-sulfonyl chloride as an off-white (trace green-grey) solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)C(C)C)(C)C.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[F:10][C:8]1[CH:7]=[CH:6][C:3]([CH2:4][OH:5])=[C:2]([NH:1][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(F)ccc1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)Nc1cc(F)ccc1CO
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a solution of 2-amino-4-fluorobenzyl alcohol from Step 1 (2.00 g, 14.17 mmol) and methylene chloride (45 mL), was added N,N,-diisopropylethylamine (3.70 g, 28.34 mmol) followed by hydrocinnamoyl chloride (4.78 g, 28.34 mmol) dropwise over 15 min under an argon atmosphere at 23° C. After 16 h, the reaction was diluted with methylene chloride (100 mL), washed with KHSO4 (1 N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was dissolved in methanol (14 mL) and NaOH (1.5 N, 14 mL) was added at 23° C. under argon. After 2 h at 23° C., the reaction was concentrated in vacuo, diluted with ether (150 mL), washed with brine (100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:hexane 1:3) to afford N-[5-fluoro-2-hydroxymethylphenyl]benzenepropanamide (3.40 g, 87.8%) as an oil: 1H NMR (CDCl3) δ 2.65 (t, J=7 Hz), 3.05 (t, J=7 Hz), 4.48 (s), 6.68-6.74 (m), 7.00-7.34 (m), 7.83-7.91 (m) 8.72 (br s). MS (EI) 273, 255, 212. IR (neat) 3500-3150, 1667 cm−1. Anal. Calc'd. for C16H16NO2F: C, 70.31; H, 5.90; N, 5.13. Found: C, 70.26; H, 6.11; N, 5.03.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)(C)C>[OH:14][C:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)C1(C)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (210 mg, 1.0 mmol), tert-butyl [(3R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (255 mg, 1.04 mmol) and triethylamine (296 μL, 2.12 mmol) in isopropyl alcohol (1 mL) was stirred at 80° C. for 2 h. The solvent was evaporated under reduced pressure and the resulting residue was purified by chromatography on silica gel eluting with 25% EtOAc in hexanes to give the sub-title compound as a yellow oil (318 mg, 74%). LCMS calc. for C20H31N4O5 (M+H)+ m/z=407.2. found 407.2.