Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].Cl[C:7]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>CO>[C:13]1([C:10]2[N:11]=[N:12][C:7]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CCS
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(-c2ccccc2)nn1
Reaction time: 0.17 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.90 g(0.01 mol) of 6-chloro-3-phenylpyridazine. The reaction solution was refluxed for 5 hours and concentrated under reduced pressure to remove methanol. 100 ml of diethyl ethers was added to the residue and vigorously stirred for 10 minutes. The materials insoluble in diethyl ether was removed and the remaining solution was washed twice with 50 ml of purified water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to remove diethyl ether. In this manner, the title compound was obtained as a white crystal.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[C:20]([CH:40]2[CH2:42][CH2:41]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH:40]2[CH2:41][CH2:42]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C2CC2)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 239, 3.19 g, 5.11 mmol) following the procedure described for Intermediate 18. The desired product was obtained as a tan foam (2.35 g, 90%).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[N:22](S(C3C=CC=CC=3)(=O)=O)[C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1)(=[O:5])[CH3:4]>CO>[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[NH:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCCNc1nc(-c2ccccc2)nc2c1cc(C(=O)O)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc2[nH]c(C(=O)O)cc12
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
A solution of sodium hydroxide in methanol (65 mL, 5M, 325 mmol) is added to a solution of the pyrrolopyrimidine 28a (6.3 g, 13.1 mmol) in methanol (35 mL). After 1.5 h, MeOH is evaporated. The residue is dissolved in 2N NaOH (200 mL) and extracted with Et2O (2×30 mL). The aqueous layer is acidified to pH≈3-4 with aq. HCl (first with 12N HCl until some solid has precipitated, then with 2N HCl until pH 3-4 is reached and no more solid precipitates). The beige solid is filtered off and dried, giving 4.345 g (12.8 mmol, 98% yield) of 30a. LC/MS analysis of this material: 95% of 30a, 3% of desacetyl-30a. This material is used without further purification. 1H-NMR (D6-DMSO): δ=1.81 (s, 3H), 3.3 (m, 2H; hidden under water peak), 3.62 (m, 2H), 7.29 (s, 1H), 7.44-7.50 (m, 3H), 8.0-8.1 (brm, 2H, NH), 8.40-8.45 (m, 2H). 1H NMR (CDCl3/CD3OD, 200 MHz): δ=1.82 (s, 3H), 3.53 (mc, 2H), 3.87 (t, J=5.7 Hz, 2H), 7.24 (s, 1H), 7.44-7.50 (m, 3H), 8.33-8.40 (m, 2H). 13C NMR (d6-DMSO, 50.3 MHz, DEPT135): δ=22.66 (+), 38.45 (−), 39.53 (−), 102.22 (Cquart), 106.11 (Cquart), 124.94 (+), 127.65 (+, 2C), 128.09 (+, 2C), 129.53 (Cquart), 138.98 (+), 152.02 (Cquart), 157.15 (Cquart), 159.21 (Cquart), 162.14 (Cquart), 169.47 (Cquart). MS (ES): m/z 339.9 (100) [MH+]. tR(method A)=5.0 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][O:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A stirred solution of 16.2 grams (0.137 mole) of 1,3-dioxan-4-ylmethanol and 16.7 grams (0.165 mole) of triethylamine in 250 mL of methylene chloride was cooled to about -20° C., and a solution of 17.3 grams (0.151 mole) of methanesulfonyl chloride in about 25 mL of methylene chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature as it stirred for one hour. The reaction mixture was then washed with water and dried with magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue. The residue was purified using column chromatography on silica gel, yielding 18.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccccc1
Yield: 35.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (60 mg, 0.37 mmol), benzenesulfonyl chloride (78 mg, 0.44 mmol) and DMAP (cat.) gave the title compound (40 mg, 36%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:5][C:6]1[C:7]([NH:13]C(=O)OC(C)(C)C)=[N:8][CH:9]=[CH:10][C:11]=1[Cl:12].[CH3:25][N:26]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N>[NH2:13][C:7]1[C:6]([O:5][C:4]2[CH:3]=[C:2]([CH:23]=[C:22]([Cl:24])[CH:21]=2)[C:25]#[N:26])=[C:11]([Cl:12])[CH:10]=[CH:9][N:8]=1
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2N)c1
Temperature: 100 °C

Procedure:
To a degassed solution of tert-butyl [3-(3-bromo-5-chlorophenoxy)-4-chloropyridin-2-yl]carbamate (651 mg, 1.50 mmol) in NMP (7 mL) was added palladium tetrakistriphenylphosphine (260 mg, 0.225 mmol) and zinc cyanide (176 mg, 1.50 mmol) and heated to 100° C. for 20 minutes. After this time, the mixture was allowed to cool to room temperature and partitioned between water (20 mL) and ethyl acetate (2×50 mL). The combined organic extracts were washed with water (20 mL), dried over MgSO4, filtered and the solvent removed in vacuo. This residue was dissolved in TFA for 10 minutes and then the solvent was removed in vacuo. This residue was partitioned between NaHCO3 (50 mL) and ethyl acetate (2×50 mL). The combined extracts were dried over MgSO4, filtered and the solvent removed in vacuo. This residue was purified by chromatography using silica gel column (120 g) and eluting with a gradient of 0-50% EtOAc in CH2Cl2 to provide the title compound. LRMS (M+1): 279.8.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][N:29]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Yield: 31.9 %

Procedure:
Following the above procedure, 2-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyrimidin-5-ylamine (60 mg, 0.15 mmol) and acetic anhydride (22.2 μL, 0.235 mmol) afford the title compound (21 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 3,4-dichlorobenzene-1-sulfonyl chloride (490 mg, 2.00 mmol) was added tert-butyl pyrrolidin-2-ylmethylcarbamate (400 mg, 2.00 mmol), followed by triethylamine (0.278 mL, 2.00 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with 1N HCl, H2O and brine, dried over Na2SO4 and decanted. The solvent was evaporated under reduced pressure and the crude product was purified on a 24 g silica gel cartridge using 0 to 100% EtOAc in hexane for 15 min, then 0 to 20% MeOH in DCM for 15 min to provide Intermediate 2A (800 mg, 1.95 mmol, 98% yield) as a white solid. HPLC/MS (Method D) RT=2.12 min, [M+1]+ 309.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccc5[nH]ccc45)ncnc32)CC1
Yield: 32 %

Procedure:
4-[4-(1H-Indol-4-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (25 mg, 32%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-hydroxyindole (TCI America, Portland, Oreg., USA; 24 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol). Mass spectrum MH+=435.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1cn2c(n1)sc1cc(C)ccc12
Yield: 57.6 %

Procedure:
Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-methyl-2-amino benzothiazole (3.2 g, 20 mmol) and ethyl bromopyruvate (4.0 g, 20.4 mmol), 3.0 g (57% Yield) of ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as brown solid. (M+H) 261.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][NH2:15])=[N:4][C:5]([CH3:13])=[N:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH:16]1([CH2:21][C@H:22]([CH2:26][N:27]([CH:36]=[O:37])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23](O)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:16]1([CH2:21][C@@H:22]([C:23]([NH:15][NH:14][C:3]2[C:2]([F:1])=[C:7]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[N:6]=[C:5]([CH3:13])[N:4]=2)=[O:24])[CH2:26][N:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[O:37])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2CCCC2)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
5-Fluoro-4-hydrazino-2-methyl-6-(1-pyrrolidinyl)pyrimidine (69 mg, 0.33 mmol), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (110 mg, 0.36 mmol), and HOAt (49 mg, 0.36 mmol) were dissolved in 2 mL of DMF. NMM (0.18 mL, 1.65 mmol) was added, followed by EDC (69 mg, 0.36 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-2-methyl-6-(1-pyrrolidinyl)-4-pyrimidinyl]hydrazino}-3-oxopropyl)[(phenylmethyl)oxy]formamide (90 mg, 55%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].[OH-].[Na+].C(O)C>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(SCc2ccc(C#N)cc2)cc(C(C)(C)C)c1O

Procedure:
A solution of 2.00 g (8.39 mmole) of the known compound 2,6-di-t-butyl-4-mercaptophenol, 1.65 g (8.39 mmole) of p-cyanobenzyl bromide, 5 ml of 1.68N sodium hydroxide and 75 ml of ethanol was heated at reflux for 48 hours. The reaction mixture was poured into water, and was then extracted with diethyl ether. The ether extract was washed with water, dried with magnesium sulfate and evaporated to give the crude product This material was purified by silica gel chromatography, eluting with 1% ethyl acetate in hexane, followed by recrystallizations from a mixture of ethyl acetate and hexane and from ethanol to give 1.1 g of 2,6-di-t-butyl-4-[(4-cyanophenyl)methylthio]phenol as white needles, m.p. 143°-145° C. Analysis: Calculated for C22H27NOS: %C, 74.7; %H, 7.7; %N, 4.0; Found %C, 75.1; %H, 8.1; %N, 4.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CC(C)CC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CC(C)C)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and isovaleryl chloride (108 μl, 0.89 mmol). The title compound was obtained as yellow powder (240 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([S:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Sc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nncs3)cc2Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Sc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[(4-methoxyphenyl)thio]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 4, 0.224 g, 0.387 mmol) in 1,4-dioxane (1 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL). The reaction was stirred under a nitrogen atmosphere at ambient temperature overnight before concentrating in vacuo. The residue was purified by silica gel flash chromatography to afford a white solid. The solid was further purified by reverse phase column chromatography (Trilution system) to afford the title compound as a solid (0.115 g, 69%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH3:36])[CH3:32]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)c1ccccc1
Product: CCNC(=O)NN(C)CC(=O)N[C@H](C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC)c1ccccc1
Yield: 50.8 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-2-phenylacetamide (Compound IV-26) 63 mg (0.15 mmol) to obtain the title compound 22 mg (25%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]1([NH:15][C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH:19]=[N:20][C:16]([NH:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:17]2)[CH:7]=1
Reactant: c1ccc(Nc2nc[nH]n2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: Clc1cc(-n2cnc(Nc3ccccc3)n2)ncn1
Temperature: 25 °C

Procedure:
To a suspension of 4,6-dichloro-pyrimidine (292 mg, 1.96 mmol ) in 5 ml anhydrous acetonitrile was added phenyl-(1H-[1,2,4]triazol-3-yl)-amine together with diisopropylamine (0.4 ml, 4.0 mmol). The mixture was heated at reflux in a sealed tube overnight. The reaction was cooled to room temperature and the solid was collected by filtration. The solid was washed with cold ether and dried under vacuum. Analytical data: LC/MS showed M+1=273.1, and M−1+271.2, retention time is 3.5 min. NMR in DMSO-d6: 9.78 (s, 1H); 9.28 (s, 1H); 8.90 (s, 1H); 7.90 (s, 1H); 7.65 (d, 2H); 7.28 (dd, 2H); 6.90 (dd, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:32]=[CH:31][C:12]2[N:13](CC3C=CC(OC)=CC=3)[C:14](=[O:21])[N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.O>[C:1]([C:9]1[CH:32]=[CH:31][C:12]2[NH:13][C:14](=[O:21])[N:15]([CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)n(CCN(C)C)c3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: O
Solvent: CC#N
Product: CN(C)CCn1c(=O)[nH]c2ccc(C(=O)c3ccccc3)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
To a solution of 1.11 g of 5-benzoyl-1,3-dihydro-3-(2-dimethylaminoethyl)-1-(4-methoxybenzyl)-2H-benzimidazol-2-one in 20 ml of acetonitrile and 7 ml of water was added 6.43 g of ceric ammonium nitrate. The reaction mixture was stirred at 60° C. for 4 hours, diluted with water and washed with ethyl acetate. After alkalization to pH 9 with 10% sodium hydroxide, the basic material was extracted with chloroform and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the crude material which was chromatographed on silica gel. Elution with chloroformmethanol (10:1) gave 40 mg of 6-benzoyl-1,3-dihydro-1-(2-dimethylaminoethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:18]=[N:17][N:16]=[N:15]1.O.[OH-].[Li+].C(O)C.Cl>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:18]=[N:17][N:16]=[N:15]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)c(C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(CC(=O)O)ccc1-n1cnnn1
Reaction time: 1 h

Procedure:
Ethyl 2-(6-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl)acetate (310 mg, 1.25 mmol) was dissolved in THF (6 mL) and water (3 mL). Lithium hydroxide monohydrate (68.31 mg, 1.628 mmol) was added. A small amount of ethanol was also added to ensure the reaction mixture was homogeneous. After 1 hr, the reaction was acidified with 2N HCl to pH ˜5-6 then extracted with a mixture of ethyl acetate/THF (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated to yield title compound: 1H-NMR (600 MHz, CDCl3) δ ppm 8.975 (s, 1H), 7.738 (d, J=8.1 Hz, 1H), 7.396 (d, J=8.1 Hz, 1H), 3.907 (s, 2H), 2.009 (s, 3H): LC-MS: M+1=220
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: ClCc1ccnc(-c2ccc(Cl)cc2)c1
Product: COc1ccc(N(Cc2ccnc(-c3ccc(Cl)cc3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-chlorophenyl)pyridine (238 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[N:7][O:6][N:5]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[N:7][O:6][N:5]=2)=[N:2][OH:1])=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COCCCNc1nonc1C(Cl)=NO
Product: COCCCNc1nonc1C(=NO)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example 1, step F, using N-hydroxy-4-[(3-methoxypropyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride and 4-fluoro-3-(trifluoromethyl)benzeneamine as the starting materials in 87% yield. LCMS for C14H16F4N5O3 (M+H)+: m/z=378.1. 1H NMR (400 MHz, DMSO-d6): δ 11.5 (s, 1H), 9.05 (s, 1H), 7.30 (dd, J=10.0, 9.6 Hz, 1H), 7.13-7.11 (m, 1H), 7.05-7.00 (m, 1H), 6.22 (t, J=5.7 Hz, 1H), 3.35-3.32 (m, 2H), 3.25-3.19 (m, 5H), 1.79-1.72 (m, 2H).