Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.CS([Cl:30])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:30][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN2CCCC[C@@H]2CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 4 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-methoxyphenethyl)piperidine (617 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (0.30 g, 2.7 mmol) and methanesulfonyl chloride (0.30 g, 2.6 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 4 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-methoxy-phenethyl)homopiperidine in the form of a light yellow oil (632 mg, 97%).
Reaction SMILES: COC([C@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OC)=[O:13])[CH2:7][C@H:6]1[C:16](=[O:22])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=O.CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[CH2:18]([N:17]([CH2:20][CH3:21])[C:16]([CH:6]1[CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]2=[O:13])[CH2:7]1)=[O:22])[CH3:19]
Reactant: CCN(CC)C(=O)[C@@H]1CN(CC(=O)OC)CC[C@@H]1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)C1CN2CCC1C(=O)C2
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A solution of 12 (159 g, 0.503 mole) in toluene (700 ml) was added dropwise over a period 2.5 hours to a solution of potassium t-butoxide (169 g, 1.51 mole) in toluene (1.9L) at 110° C. under a nitrogen condition. The mixture was heated at reflux for 1 hour and cooled down to room temperature. Water (400 ml) was added then the layers were heated at reflux for 2 hours. After the organic layer was separated, the aqueous layer was neutralized and extracted with EtOAc for 15 hours with continuous extraction apparatus. The combined extracts were dried over MgSO4 and concentrated down. Recrystallization from EtOH gave 13 (34.6 g, 31%) as a colorless crystal. The stereochemistry was determined by X-Ray analysis, 13C and NMR.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1)=[CH2:16])[S:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])=[O:4].O.O.O.C([O-])(=[O:32])C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl>[O:32]1[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[N:18]=2)([CH2:14][N:2]([CH3:1])[S:3]([CH:6]=[CH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:4])=[O:5])[CH2:16]1
Reactant: C=C(CN(C)S(=O)(=O)C=Cc1ccccc1)c1cccc(C(F)(F)F)n1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(CC1(c2cccc(C(F)(F)F)n2)CO1)S(=O)(=O)C=Cc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 119.5 %

Procedure:
A mixture of 1.1 g of 3-(N-methyl-N-styrylsulfonylamino)-2-(6-trifluoromethylpyridin-2-yl)propene, 0.20 g of sodium acetate trihydrate, 2.19 g of 40% peracetic acid and 11 ml of chloroform was stirred at 60° C. for 5 hours. After the reaction mixture was cooled to room temperature, 10 ml of carbon tetrachrolide was added thereto, and the whole mixture was subsequently washed with water, an aqueous solution of 10% sodium bisulfite, a 2N aqueous solution of sodium hydroxide, water and saturated saline solution in that order and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate 15:1) to obtain 0.70 g of Compound No. 4 in Table 1.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]2[CH:8]([CH:9]=1)[C:7](=[CH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]2)[CH3:2].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:35]([CH3:38])([O-:37])=[O:36]>>[CH2:1]([C:3]1[CH2:4][CH:5]2[CH:8]([CH:9]=1)[C:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])([CH2:38][N+:35]([O-:37])=[O:36])[CH2:6]2)[CH3:2]
Reactant: CCC1=CC2C(=CC(=O)OC(C)(C)C)CC2C1
Reactant: C[N+](=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 7 h

Procedure:
Tert-butyl 3-ethylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.32 g, 5.63 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL, 7.3 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 7 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.39 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[Si:25]([O:32][CH2:33][CH2:34][CH:35]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:35][CH2:34][CH2:33][O:32][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(NCCCO[Si](C)(C)C(C)(C)C)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3.3 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (0.2 g, 6 mmol) and 3-(tert-butyldimethylsilyloxy)propionaldehyde (0.25 g, 13 mmol) in CH2Cl2 (10 mL) and MeOH (5 mL) was stirred at room temperature for 15 min and then NaCNBH3 (57 mg, 1.5 eq) was added. The reaction mixture was stirred at RT overnight and then concentrated under vacuo. The residue was purified by preparatory TLC to give 98 mg 3-(1-methylindol-3-yl)-4-[3-(3-tert-butyldimethylsilyloxypropylamino)phenyl]-1H-pyrrole-2,5-dione (32%) MS (LSIMS): (M+H)+ 490, MP: 58-65° C.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([O:13][C:1](=[O:14])[C:2]1[CH:3]=[C:4]([O:5][CH3:6])[C:7]([OH:8])=[C:9]([O:10][CH3:11])[CH:12]=1)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Product: C#CCOC(=O)c1cc(OC)c(O)c(OC)c1

Procedure:
By utilizing the procedure of Example 5, by reacting syringic acid and propargyl bromide, there is obtained syringic acid propargyl ester, F. P. 105°-106° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.C(OCC)C.[NH3:37]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)[S:6][C:5]=1[C:3]([NH2:37])=[O:2])[CH3:12]
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CO
Solvent: CCOCC
Product: CC(Oc1cc(-n2cnc(Nc3ccccc3)n2)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 27 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl ester (66 mg, 0.15 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The solvent was removed in vacuo and the product isolated by column chromatography (10% MeOH/DCM) followed by tritruation from diethyl ether to give the title compound as an off-white solid (17 mg, 0.04 mmol, 27%); 1H NMR (400 MHz, d-6 DMSO) 1.72 (3H, d), 5.88 (1H, q), 6.88 (1H, t), 7.03 (1H, br s), 7.26 (1H, s), 7.30 (2H, t), 7.36-7.43 (2H, m), 7.52 (1H, dd), 7.57 (2H, d), 7.66 (1H, dd), 7.75 (1H, br s), 9.02 (1H, br s), 9.65 (1H, s).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2N)=[N:2]1.N(OCCCC)=O.[CH3:21][S:22]C>[Cu](Cl)Cl>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:7]([S:22][CH3:21])[C:6]=1[C:3]1[CH2:4][CH2:5][O:1][N:2]=1
Reactant: CSC
Reactant: Cc1cccc(N)c1C1=NOCC1
Agent: Cl[Cu]Cl
Agent: CCCCON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
25 g (0.14 mol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline and 0.2 g of copper(II) chloride are initially charged in 200 ml of dimethyl sulfide, and 16.1 g of n-butyl nitrite (0.15 mol) are added dropwise at 55-62° C. The mixture is then stirred at 60° C. for 0.5 hours. For work-up, the mixture is then washed with dilute hydrochloric acid and water and then concentrated under reduced pressure. This gives 26.3 g (91%) of a dark oil which solidifies after a while (content according to HPLC 96%). The product can be purified further by trituration with methyl tert-butyl ether.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([O:24][CH3:34])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)C(C)(C)CC(=O)O)cc2)ccc(C(C)=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(C)(C)CC(=O)OC)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from Step C (250 mg), 4-(3-bromopropyl)-2-hydroxy-3-propylacetophenone (315 mg), and potassium carbonate (410 mg) in methyl ethyl ketone (10 ml) was refluxed under N2 for 4 hours then stirred at ambient temperature for 18 hours. The mixture was filtered, washed with brine, evaporated to dryness and the resulting oil was Purified by chromatography on silica gel to provide the title compound as an oil. NMR (CDCl3) 0.90 (3H, t), 1.43 (6H, s), 1.52 (2H, m), 2.30 (2H, m), 2.50 (3H, s), 2.55 (2H, m), 2.75 (2H, s), 3.57 (3H, s), 4.18 (4H, m), 6.41 (1H, d), 6.88 (2H, d), 7.53 (1H, d), 7.72 (2H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:14][C:13]3=[CH:15][S:16][CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:11]2[C:12]3=[CH:17][S:16][CH:15]=[C:13]3[N:14]=[C:10]2[S:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: Cc1ccc(CSc2nc3cscc3[nH]2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(CSc2nc3cscc3n2C(=O)Oc2ccc([N+](=O)[O-])cc2)nc1

Procedure:
The title compound was prepared in analogy to Example 17 from 2-(5-methyl-2-picolylmercapto)-1H-thieno[3,4-d]imidazole and p-nitrophenyl chloroformate. After working up and chromatography on silica gel using toluene/ethyl acetate (1:1), the appropriate fractions were crystallized from ethyl acetate, and the title compound was obtained. Melting point 165°-168° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][O:13][CH3:14])=[NH:11])[N:3]=1.[CH3:15][O:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])(=[O:19])=[O:18].O>N1C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:9][C:10]([NH:11][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([O:16][CH3:15])(=[O:19])=[O:18])(=[O:28])=[O:27])=[N:12][O:13][CH3:14])[N:5]=1
Reactant: CONC(=N)Nc1nc(C)cc(C)n1
Reactant: COS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=C(Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1S(=O)(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.7 %

Procedure:
N-(4,6-Dimethylpyrimidin-2-yl) N'-methoxyguanidine (9.75 g) was a dissolved in pyridine (200 ml), and 2-methoxysulfonylbenzenesulfonyl chloride (13.5 g) was added to the solution. The mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and extracted with methylene chloride. The organic layer was washed with a 1N aqueous solution of hydrochloric acid, and dried over anhydrous sodium sulfate. Methylene chloride was evaporated under reduced pressure, and the residue was recrystallized from methanol to give 10 g of the desired N-(4,6-dimethylpyrimidin-2-yl) N'-(2-methoxysulfonylbenzenesulfonyl) N"-methoxyguanidine represented by the following formula. mp. 130°-138° C. ##STR21##
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[C:4]2[N:23]=[CH:24][CH:25]=[CH:26][C:3]=12.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:15])[CH2:10][C@H:9]3[CH3:22])=[C:4]3[N:23]=[CH:24][CH:25]=[CH:26][C:3]=23)=[CH:31][CH:30]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(CO)cc2)c2cccnc12
Yield: 56.8 %

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (180 mg, 489 μmol), 4-(hydroxymethyl)phenylboronic acid (112 mg, 734 μmol), tetrakis(triphenylphosphine)palladium (28 mg, 24 μmol), and 2 M sodium carbonate (489 μl, 979 μmol) yielded (R)-(4-(5-(4-(hydroxymethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 82 (122 mg, 57% yield) after chromatographic purification. MS 439.2 (calc'd) 440.2 (M+H, found).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[C:8](Br)[C:7]([C:16]#[N:17])=[N:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:8]1[C:7]([C:16]#[N:17])=[N:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9]=1[CH2:10][C:11]([OH:14])([CH3:13])[CH3:12]
Reactant: Nc1ccccc1B(O)O
Reactant: CCCCn1nc(C#N)c(Br)c1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CCCCn1nc(C#N)c(-c2ccccc2N)c1CC(C)(C)O

Procedure:
A modification of the method described in Part H of Example 1255 was used to treat 1-butyl-4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (2.7 g, 9.2 mmol). Two equivalents of 2-aminophenylboronic acid hydrochloride (3.2 g, 18.4 mmol) and 2 mol % dichlorobis(triphenylphosphine)palladium(II) (0.126 g, 0.18 mmol) were added at the beginning of the reaction, and the reaction was heated at reflux for five hours. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with 0 to 50% ethyl acetate in hexanes to provide 4-(2-aminophenyl)-1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[CH3:5][S:6][C:7]1[S:11][C:10]([N:12]=[C:1]=[O:2])=[N:9][N:8]=1
Reactant: O=C(Cl)Cl
Reactant: CSc1nnc(N)s1
Solvent: CCOC(C)=O
Product: CSc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylthio-2-amino-1,3,4-thiadiazole (45 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH2:17])[CH:11]=[C:10]([Br:18])[N:9]=1.C(N(CC)CC)C>O>[CH2:5]([O:4][C:2](=[O:3])[NH:17][C:12]1[CH:11]=[C:10]([Br:18])[N:9]=[C:8]([Br:7])[C:13]=1[N+:14]([O-:16])=[O:15])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of ethyl chloroformate (5.96 g) in anhydrous 2-methyl THF (50 ml) was added drop-wise to a solution of 2,6-dibromo-3-nitro-pyridin-4-ylamine (15.00 g) and triethylamine (10.1 g) in anhydrous 2-methyl THF (100 ml) at 0° C., keeping the addition rate such that the reaction temperature did not rise above 5° C. The reaction mixture was allowed to warm to room temperature then left to stir under nitrogen for 1 hour. A further portion of ethyl chloroformate (0.54 g) was added and the mixture was left to stir for a further 1 hour. Water (50 ml) was added and the layers separated. The aqueous layer was extracted with EtOAc (50 ml) and the combined organics were dried (MgSO4) and evaporated to a brown solid. This solid was pre-absorbed onto silica (˜19 g) then columned on Isco Companion on a silica column (330 g, Redisep), eluting with EtOAc:heptane. The gradient was kept isocractic at 10:90 for 1 column volume (CV), then increased linearly from 10:90 to 30:70 over 6 CVs. This provided the title compound (12.6 g) as a pale yellow foamy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([O-])=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1N
Yield: 97.6 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[2-nitro-5-(4-phenylphenoxy)phenyl]-N-methylcarbamate (5.32 g), palladium on carbon (10%, 0.68 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (4.82 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[F:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:23][C:22]3[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:21]=3[F:20])=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)OC)cnc12
Yield: 47 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (4.0 g, 14.0 mmol) obtained in Example 21, step 2 and 2-fluoro-5-methylaniline (2.4 mL, 20.9 mmol), the title compound (2.45 g, 47%) was obtained.
Reaction SMILES: O[C@@H]1CC[N:5](C(OCC2C=CC=CC=2)=O)[C@H](C(OC)=O)C1.[CH3:22][O:23][C:24]([CH:26]1[CH2:31][CH:30]([O:32][C:33]2[C:42]3[C:37](=[C:38]([CH3:45])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[C:35]([C:46]3[S:47][CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[N:50]=3)C=2)[CH2:29][CH2:28][N:27]1[C:55](OCC1C=CC=CC=1)=O)=[O:25]>>[CH3:22][O:23][C:24]([CH:26]1[CH2:31][CH:30]([O:32][C:33]2[C:42]3[C:37](=[C:38]([CH3:45])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[C:35]([C:46]3[S:47][CH:48]=[C:49]([C:51]([F:53])([F:52])[F:54])[N:50]=3)[N:5]=2)[CH2:29][CH2:28][N:27]1[CH3:55])=[O:25]
Reactant: COC(=O)C1CC(Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CCN1C(=O)OCc1ccccc1
Product: COC(=O)C1CC(Oc2nc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CCN1C
Yield: 60 %

Procedure:
Compound 22 was synthesized from compounds 12 and 206 as a yellow powder in 60% yield according to the procedure as described for compound 13. MS (ESI, EI+) m/z=617 (MH+).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]3[N:42]=[C:41]([C:43]4[C:51]5[C:46](=[CH:47][CH:48]=[C:49]([NH2:52])[CH:50]=5)[N:45]([CH:53]5[CH2:58][CH2:57][CH2:56][CH2:55][O:54]5)[N:44]=4)[NH:40][C:39]=3[CH:59]=2)[CH2:30][CH2:29]1>CN(C=O)C>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:52][C:49]1[CH:50]=[C:51]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)[N:44]=[C:43]2[C:41]1[NH:42][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)=[CH:59][C:39]=2[N:40]=1)=[O:6]
Reactant: O=C(O)C1CC1(F)F
Reactant: Nc1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(CN4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
2,2-Difluorocyclopropane carboxylic acid (3 mg, 0.024 mmol), HOBt (5 mg, 0.037 mmol), EDC (6.6 mg, 0.035 mmol) and sodium bicarbonate (2 mg, 0.024 mmol) were added to a solution of 3-(6-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.023 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) yielded the title compound (10 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.62 (s, 1H), 7.75-7.66 (m, 4H), 7.34 (d, 1H, J=8.0 Hz), 5.94 (dd, 1H, J=2.8 and 9.6 Hz), 4.01 (m, 3H), 3.85 (m, 1H), 3.77 (m, 4H), 2.81 (m, 4H), 2.68 (m, 1H), 2.18-2.10 (m, 3H), 1.91-1.83 (m, 3H), 1.71 (m, 2H); ESI-MS [M+H]+: 537.2.