Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17](=N)[NH2:18].C(=O)([O-])[O-].[K+].[K+].O.C(S(C1[CH2:37][C:36]([CH3:39])([CH3:38])[O:35]N=1)(=O)=O)C>C(O)C.CN(C)C=O>[F:2][CH:3]([F:20])[O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[CH2:15][S:16][C:17]1[CH2:37][C:36]([CH3:39])([CH3:38])[O:35][N:18]=1
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Reactant: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 1.93 g (5.00 mmol) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrobromide in 10 ml of ethanol were added 0.83 g (6.00 mmol) of anhydrous potassium carbonate and 5 ml of water, followed by 30 minutes of stirring at room temperature. Thereto were added a solution of 0.95 g (5.00 mmol) of 3-ethanesulfonyl-5,5-dimethyl-2-isoxazoline in 5 ml of N,N-dimethylformamide and 0.83 g (6.00 mmol) of anhydrous potassium carbonate at room temperature, followed by further 3 hours of stirring at 50° C. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. The obtained residue was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1.55 g (yield: 86.1%) of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(OCC)(=O)C>[C:24](=[O:25])([O:26][CH2:27][CH3:28])[O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[Cl:9]
Reactant: CCOC(=O)Cl
Reactant: Oc1c(Cl)cc(-c2ccccc2)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1c(Cl)cc(-c2ccccc2)cc1Cl
Reaction time: 8 h
Yield: 90.7 %

Procedure:
40.6 g (0.17 mol) of 3,5-dichloro-4-hydroxybiphenyl (prepared according to J. C. Colbert et al., JACS 56, 202 (1934)) and 17.2 g (0.17 mol) of triethylamine are dissolved in 170 ml of ethyl acetate and admixed dropwise with 18.4 g (0.17 mol) of ethyl chloroformate at 10° C. The reaction solution is stirred overnight and washed with water, and the organic phase is concentrated. For further purification, the crude product (51.2 g) is chromatographed over silica gel using the system chloroform. 48 g (yield 90.8% of theory) of (2,6-dichloro-4-phenyl-phenyl) ethyl carbonate are obtained as an oil, log p (pH 7.5): 4.65.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Cl:13])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=S(Cl)Cl
Product: Oc1ccc(CCl)cn1

Procedure:
A 100 ml RBF was charged with 6-hydroxynicotinic acid (4 g) and 20 ml of thionyl chloride. The mixture was refluxed for 1 hr. Excess thionyl chloride was then evaporated in vacuo to obtain the 6-hydroxynicotinyl chloride. A 200 ml RBF was charged with 1.13 g of 6-hydroxynicotinyl chloride in 100 ml of methylene chloride, cooled and stirred at 0° C. Piperidine (8.6 mM=0.85 ml) in 10 ml methylene chloride was added dropwise and the resulting mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under vacuum. To the residue was added 25 ml of methylene chloride and stirred at 30° C. for 5 minutes. Solid was filtered and residue was chromatographed using CH2Cl2:MeOH:NH3=200:10:1. The product was recrystallized from CH2Cl2 and petroleum ether to furnish 0.92 g (62%) of product. 1H NMR (CDCl3, 400 MHz) δ: 7.61 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.55 (d, J=8.6 Hz, 1H), 3.50 (bs, 4H), 1.65 (m, 2H), 1.57 (m, 4H). 13C NMR (CDCl3, 400 MHz) δ: 166.5, 164.8, 141.3, 135.7, 119.7, 116.1, 26.0, 24.4. IR (CHCl3) cm−1: 3346, 3050, 3004, 1655, 1615, 1473, 1115, 841, 780, 627. HREIMS m+/z (%): C11H14N2O2 (calc)=206.1055; C11H14N2O2 (obs)=206.1061 (70).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([N:11]1[C:19]2[N:18]=[CH:17][N:16]([CH3:20])[C:15]=2[C:14](SC)=[N:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[CH2:4]([N:11]1[C:19]2[N:18]=[CH:17][N:16]([CH3:20])[C:15]=2[C:14]([NH:2][NH2:3])=[N:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: CSc1nc(=O)n(Cc2ccccc2)c2ncn(C)c12
Solvent: O
Product: Cn1cnc2c1c(NN)nc(=O)n2Cc1ccccc1
Temperature: 25 °C

Procedure:
After 16.0 ml of hydrazine hydrate was added to 2.00 g (6.99 mmol) of Compound h prepared in Reference Example 8, the mixture was stirred at room temperature for day and night. The reaction mixture was poured onto 300 ml of water and the precipitates were taken out by filtration and washed with ether to give 1.60 g (yield, 85%) of Compound p as a white powder.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH2:27][CH2:26][C:24]2[CH:25]=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6]4)=[CH:17][N:16]=3)=[O:19])[NH:22][N:23]=2)[CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: C=CCN1CCCNCC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Solvent: CO
Product: C=CCN1CCCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
1-Prop-2-enyl-1,4-diazepane (224 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (271 mg, 69%) as a yellow solid.
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].[CH3:8][S:9]([CH3:11])=[O:10]>>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[CH3:8][S+:9]([CH3:5])([CH3:11])=[O:10]
Reactant: COS(=O)(=O)OC
Reactant: CS(C)=O
Product: COS(=O)(=O)[O-]
Product: C[S+](C)(C)=O

Procedure:
which comprises contacting dimethyl sulphoxide with dimethyl sulphate at a temperature of at least 100° C., whereby to form trimethyloxosulphonium methyl sulphate of the formula
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[ClH:12].Cl.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[OH2:11].[ClH:32].[ClH:12].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])[CH2:24][CH2:23]2)=[CH:27][CH:28]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Product: O
Yield: 172.2 %

Procedure:
The procedure described in Example 29 was followed, using 4-(methylthio)phenyl isocyanate (10.0 g; 60.5 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (22.8 g; 60.5 mmole), methylene chloride (400 ml), and triethylamine (25.8 ml; 185 mmole). Recrystallization from methanol/water provided the title compound (27.3 g; 89% yield) as colorless crystals, m.p. 212°-214° C.
Reaction SMILES: [OH-:1].[K+].[OH-].[Na+].S([C:9]1[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12](=[CH:16][CH:17]=1)[C:13]([OH:15])=[O:14])(O)(=O)=O>>[OH:1][C:9]1[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12](=[CH:16][CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccc(O)cc1C(=O)O
Temperature: 0 °C

Procedure:
In a stainless steel beaker with a steel stirrer a mixture of 300 g KOH (5.36 mole), 150 g NaOH (3.75 mole), 120 g of a 50% aqueous solution of 4-sulfophthalic acid (~0.25 mol) was heated for 4 hr on an oil bath. It was then cooled such that it remained molten and poured into 600 ml ice + water. With cooling it was neutralized to pH 9.0 without noting any precipitate of m-hydroxybenzoic acid by-product. It was then acidified, evaporated to dryness in a rotary evaporator and extracted in a Soxhlet to separate the soluble product from the insoluble inorganics. Crude yield 26 g (59%, M.P. 175°-180° C. Recrystallized from ~2 vol boiling water. Yield 19.5 g (44%), M.P. 201°-3° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:19])[S:18][C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26](=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1>>[Cl:35][C:30]1[CH:29]=[C:28]([CH2:27][C:26](=[O:36])[CH2:25][NH:24][C:20]([C:10]2[N:11]=[C:12]3[S:18][C:17]([CH3:19])=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: Cc1cn2c(=O)c(OCc3ccccc3)c(C(=O)O)nc2s1
Reactant: NCC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: Cc1cn2c(=O)c(OCc3ccccc3)c(C(=O)NCC(=O)Cc3ccc(Cl)c(Cl)c3)nc2s1

Procedure:
Adapted from example 2 using the product of example 1 and 1-amino-3-(3,4-dichloro-phenyl)-propan-2-one hydrochloride.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:22])[C:7](=[O:21])[CH2:8][CH2:9][N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35]N(C)[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.[C:43]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(O)C>[CH:31]1([NH:30][C:28](=[O:29])[C:27]2[CH:38]=[CH:39][C:24]([NH:23][C:2]3[N:12]=[C:11]4[C:5]([N:6]([CH3:22])[C:7](=[O:21])[CH2:8][CH2:9][N:10]4[CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:4][N:3]=3)=[C:25]([O:40][CH3:41])[CH:26]=2)[CH2:32][CH2:33][CH2:43][CH2:35][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)CCN(CCN2CCCCC2)c2nc(Cl)ncc21
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(C(=O)NC2CCCCC2)ccc1Nc1ncc2c(n1)N(CCN1CCCCC1)CCC(=O)N2C
Yield: 26.7 %

Procedure:
10-chloro-6-methyl-2-[2-(1-piperidyl)ethyl]-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 159; 90 mg, 0.28 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 83 mg, 0.34 mmol) and p-toluenesulphonic acid monohydrate (107 mg, 0.56 mmol) were heated together in IPA (4 mL) by microwave irradiation at 150° C. for 20 minutes. The reaction mixture was loaded onto an SCX-2 (5 g) column pre-wet with methanol; the column was washed with methanol and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated. The resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (40 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: Oc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Reactant: BrCCCCBr
Product: BrCCCCOc1ccc2c(ccn2-c2ccc(Br)cc2)c1

Procedure:
In analogy to example 3.1, 1-(4-Bromo-phenyl)-1H-indol-5-ol and 1,4-dibrombutane were converted to yield 5-(4-Bromo-butoxy)-1-(4-bromo-phenyl)-1H-indole as light yellow solid, mp 80-81° C., MS: 421 (M, 2Br).
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].Cl.[C:9](=[NH:14])(OCC)[CH3:10].[CH2:15](N)[CH2:16][CH3:17]>C(#N)C>[NH2:7][C:6]1[N:14]([CH2:15][CH2:16][CH3:17])[C:9]([CH3:10])=[N:1][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: CCOC(C)=N
Reactant: N#CC(N)C(N)=O
Reactant: CCCN
Agent: Cl
Solvent: CC#N
Product: CCCn1c(C)nc(C(N)=O)c1N
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
A mixture of 2-amino-2-cyanoacetamide (prepared as described in WO 94/00453; 3.6 g, 36.4 mmol) and ethyl acetimidate hydrochloride (4.50 g, 36.4 mmol) in acetonitrile (85 mL) was stirred at 50° C. for an hour, then cooled to 0° C., and stirred for a further hour. The reaction mixture was filtered, and n-propylamine (3.02 mL, 36.4 mmol) added. The solution was stirred at room temperature for an hour, and left to stand for a further 16 hours. The resulting precipitate was filtered, washed with acetonitrile, then dichloromethane and dried under vacuum to afford the title compound as a solid (3.0 g, 45%).
Reaction SMILES: [NH2:1][C@@H:2]([CH:19]([CH3:21])[CH3:20])[C:3]([NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:20][CH:19]([CH3:21])[C@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2)[C:3]([NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CC(C)[C@H](N)C(=O)Nc1cccnc1Nc1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of (S)-2-amino-3-methyl-N-(2-phenylaminopyridin-3-yl)butyramide (3.0 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (720 mg, 3.0 mmol) and DIPEA (2.6 mL, 15.0 mmol) in n-butanol (12 mL) was heated at 100° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound (821 mg, 68% over two steps). LCMS (Method J): RT 1.75 min [M+H]+ 403.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[CH3:38][C:39]1[N:47]=[C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:41]([C:40]2[C:39]([CH3:38])=[N:47][C:46]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:50][CH:49]=3)=[CH:45][CH:44]=2)=[O:42])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-[3-chloro-4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:22])[CH3:20])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N(C)C

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and dimethylamine (11 ml, 33% in EtOH, 61.0 mmol) in DMSO (35 mL) at 50° C. according to the general procedure C. Obtained as a yellow solid (3.50 g, 97%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (64.3 mg, 0.34 mmol, from Step B) and (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT (54.5 mg, 0.42 mmol) at 0° C. The reaction was stirred at 0° C. for 10 min, then EDC (96.6 mg, 0.50 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 14 h. The mixture was concentrated and purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) to give 115 mg of the title compound as a foamy solid.
Reaction SMILES: C(OC([NH:8][C:9](=[NH:47])[C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[NH:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[NH:40][CH2:41][C:42]([OH:44])=[O:43])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[C:9]([C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[NH:33][C:34](=[O:46])[NH:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[NH:40][CH2:41][C:42]([OH:44])=[O:43])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)(=[NH:8])[NH2:47]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCNC(=O)NCC(=O)O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCNC(=O)NCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 60 %

Procedure:
A suspension of {3-[2-(3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-ethyl]-ureido}-acetic acid ((Example 196: step b) 0.025 g, 0.035 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1.00 mL) and stirred at room temperature 1.2 h. Solvents were removed in vacuo. Preparatory HPLC (10–80% acetonitrile in 1% TFA/water over 30 min.) afforded the product [3-(2-{3-[3′-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic acid trifluoroacetate (0.013 g, 60%) as a white glassy solid. 1H NMR (CD3CN): δ 8.099 (s, 1H), 8.048 (d, 1H, J=9.6 Hz), 7.815 (t, 1H, J=1.6 Hz), 7.709 (t, 1H, J=8.0 Hz), 7.575 (d, 1H, J=7.6 Hz), 7.498 (d, 1H, J=8.0 Hz), 7.295 (t, 1H, J=7.6 Hz), 7.161 (d, 1H, J=8.0 Hz), 3.756 (s, 2H), 2.979 (s br, 4H), 2.681 (s, 3H), 2.079 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1Cl.[Na].[C:14](O)(=[O:16])C>CO.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[O:16][CH3:14]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: CC(=O)O
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C)nc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2-chloro-6-methyl-nicotinic acid methyl ester (10.4 g, 56.52 mmol) in MeOH under nitrogen is added a solution of sodium (2.58 g, 113.04 mmol) in methanol (80.0 mL) (sodium metal is dissolved in methanol under a nitrogen atmosphere) at room temperature. The reaction mixture is refluxed overnight. The reaction is cooled to room temperature and the pH is adjusted to pH=7 with acetic acid. The reaction mixture is diluted with ethyl acetate (100 mL) and water (30 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over Na2SO4, filtered, and concentrated to give crude product. Yield: 7.25 g (71%). 1H NMR (400 MHz, CDCl3), δ8.066-8.047 (d, J=7.6 Hz, 1H), 6.782-6.764 (d, J=7.2 Hz, 1-1H), 4.029 (s, 3H), 3.879 (s, 3H), 2.483 (s, 3H); ES/MS m/z 182.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=[C:12]([CH3:26])[C:11]=2[C:10](=O)[CH2:9]1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:13]=[C:12]([CH3:26])[C:11]=2[C:10](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1nn(CCCc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(CCCc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 175.4 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-1-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.11 g), aminoguanidine hydrochloride (0.048 g), concentrated hydrochloric acid (0.073 ml), water (0.073 ml) and ethanol (10 ml) was refluxed for 8 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-1-(3-phenylpropyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 153) (0.12 g) as colorless crystals.