Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].[CH3:26][C:27]1[C:31]([S:32]([NH2:35])(=[O:34])=[O:33])=[C:30]([CH3:36])[O:29][N:28]=1>>[CH3:26][C:27]1[C:31]([S:32]([NH:35][C:17]([C:14]2[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]3[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:19])(=[O:34])=[O:33])=[C:30]([CH3:36])[O:29][N:28]=1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Reactant: CCN(Cc1cc(Br)ccc1OCC(C)C)c1ccc(C(=O)O)nn1
Product: CCN(Cc1cc(Br)ccc1OCC(C)C)c1ccc(C(=O)NS(=O)(=O)c2c(C)noc2C)nn1

Procedure:
The title compound was prepared from 6-[5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino]pyridine-3-carboxylic acid (example 9) and 3,5-dimethylisoxazol-4-ylsulphonamide using a similar method to that of example 14.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][C:15](O)=[O:16])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]([N:13]1[CH2:14][C:15](=[O:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[S:10])[CH3:12]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 55.5 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 7.65 g of 4-fluorophenyl-isothiocyanate, 9.32 g of N-ethyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The title compound (6.6 g) was obtained as a pink solid, m.p. 149°-151° C. Anal. Calcd. for. C11H11F N2O S: C, 55.45; H, 4.65; N, 11.76. Found: C, 55.31; H, 4.51; N, 10.82. Mass spectrum (EI, M.+) m/z 238.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[F:24][C:20]1[CH:19]=[C:18]([N:13]2[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(F)c3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Solvent: C1COCCO1
Product: Fc1cccc(-n2nc3c(c2-c2ccccc2)CCNCC3)c1
Yield: 34.6 %

Procedure:
The title compound (37.6 mg) was prepared from 339.2 mg of 2-(3-fluoro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made as in Example 176, Steps A and B from (3-fluoro-phenyl)-hydrazine) as described in Example 196, using 1,4-dioxane as the solvent. MS (ESI): exact mass calculated for C19H18FN3, 307.15; found, m/z 308.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39-7.35 (m, 3H), 7.20-7.14 (m, 3H), 7.00-6.96 (m, 1H), 6.94-6.86 (m, 2H), 3.13-3.09 (m, 2H), 3.06-3.02 (m, 2H), 3.01-2.96 (m, 2H), 2.69-2.66 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.C([Li])CCC.CN(C)[CH:27]=[O:28]>O1CCCC1>[CH3:19][C:16]1[O:15][C:14]([CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH:27]=[O:28])=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3c(C=O)cccc3n2)o1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (example 3, step A, 700 mg, 2.2 mmol) was dissolved in 30 mL tetrahydrofuran and cooled to −78° C. n-Butyllithium (3.45 mL, 1.6 M in hexane, 5.5 mmol) was added and the reaction mixture was allowed to warm to −10° C. Stirring was continued at −10° C. for 45 minutes. The reaction was cooled again to −78° C. and N,N-dimethylformamide (404 mg, 5.5 mmol) was added. The reaction mixture was slowly warmed up and quenched at 5° C. by addition of 100 mL water. The mixture was extracted three times with ethyl acetate (100 mL each). The organic phases were pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->50:50 gradient). 2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbaldehyde was obtained as a brown oil (242 mg, 41%), MS: m/e=267.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([O:18]C)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1nc(Br)ccc1OCc1ccccc1
Yield: 97.9 %

Procedure:
A solution of methyl 3-(benzyloxy)-6-bromopicolinate (2.0 g, 6.20 mmol) and LiOH.H2O (0.71 g, 18.60 mmol) in 1,4-dioxane/H2O (100 mL/20 mL) was stirred at 40° C. overnight. The mixture was filtered and the filtrate was acidified to pH=3 by aqueous HCl (2 M) and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to afford the product of 3-(benzyloxy)-6-bromopicolinic acid (1.87 g, yield: 97.9%) without further purification. 1H-NMR (CDCl3, 400 MHz) δ 7.52˜7.54 (m, 1H), 7.39˜7.41 (m, 2H), 7.24˜7.34 (m, 4H), 5.24 (s, 2H). MS (M+H)+: 308/310.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:24])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: CC(C)(N)CO
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC(C)(C)CO)cn2)cn1
Yield: 63 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using 2-amino-2-methylpropan-1-ol instead of isopropylamine, to the title compound (56 mg, 63%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC then silica, ethyl acetate). MS: m/e=436.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cccc(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,3-dichlorobenzene and isolated as colorless gum (6.7 mg, 37%). MS (m/e): 441.3 (MH+).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[NH2:14][CH2:13][CH2:12][NH:15][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: CCOC(=O)c1cccnc1
Reactant: NCCN
Product: NCCNC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (21.9 g.) and ethylenediamine (30 ml.) was heated to 100° C. for 16 hours under an atmosphere of argon. Excess ethylenediamine was removed by distillation in vacuo and the residue was dissolved in water (100 ml.) The insoluble material [bis(carboxamido)derivative] was removed by filtration. Evaporation of the filtrate, addition of toluene (50 ml.) followed by re-evaporation gave crude N-(2-aminoethyl)pyridine-3-carboxamide (26.5 g.) as its oily free base, essentially pure by TLC (Si02 : 10% MeOH/CHCl3) and which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]([N:5]([CH2:4][C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[NH:1][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[CH2:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 101.8 %

Procedure:
The procedure of Example 33 was followed using the product from Example 32 (500 mg, 1.268 mmol), triethylamine (0.884 ml, 6.34 mmol), and benzoyl chloride (0.324 ml, 2.79 mmol) in methylene chloride (60 ml) to give 620 mg (100%) of the product.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[C:8]2([O:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:7]1=O)[C:3]#[N:4].N.C1COCC1.[H][H]>[Ni].CCO>[CH3:1][C:2]1([CH3:29])[CH2:5][N:6]2[C:14]3[CH:13]=[CH:12][C:11]([S:15]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)(=[O:16])=[O:17])=[CH:10][C:9]=3[C:8]3([O:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:7]2=[N:4][CH2:3]1
Reactant: [H][H]
Reactant: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CN=C2N(C1)c1ccc(S(=O)(=O)N3CCCC3)cc1C21OCCCO1
Temperature: 135 °C
Yield: 45.1 %

Procedure:
A mixture of 2,2-dimethyl-3-[2′-oxo-5′-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl]propanenitrile (0.69 g, 1.64 mmol) and wet Raney Nickel (0.70 g) in 2M EtOH.NH3 (50 mL) and THF (20 mL) was hydrogenated in a Parr hydrogenation bottle (500 mL) at 541 b/in2 hydrogen for 67 hr. The Raney Nickel was removed by filtration through Sulka Floc and the filtrate was poured into a steel pressure vessel, diluted with 2M EtOH.NH3 (50 mL) and THF (20 mL) and heated at 135° C. for 22 hr. The reaction was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (98.5/1/.05) to give the title compound as a white solid (0.300 g, 45% yield). NMR: consistent. MS: (API-ES+) m/z 406 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](C(OCC)=O)([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:2].[Cl-].[Li+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C)(CC=C(C)C)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)CC=C(C)C
Temperature: 0 °C

Procedure:
85.3 g of 2-ethoxycarbonyl-2,5-dimethyl-4-hexenoic acid ethyl ester was dissolved in 645 ml of dimethyl sulfoxide and combined in succession with 29.7 g of lithium chloride and 6.3 ml of distilled water. The reaction mixture was thereafter heated a total of 13 hours to 200° C. and subsequently--after cooling--poured on 1 liter of ice water. The aqueous phase was extracted three times with respectively 500 ml of methylene chloride. The combined organic extracts then were washed twice with water, dried over magnesium sulfate, concentrated on a forced circulation evaporator, and distilled under vacuum, thus isolating 53.1 g, bp13 75°-78° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:30])=[O:29])[CH2:36][CH2:35]1
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Reactant: CN1CCN(S(=O)(=O)CCCCl)CC1
Product: CN1CCN(S(=O)(=O)CCCOc2cccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)CC1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 1-[(3-chloropropyl)sulfonyl]-4-methylpiperazine (Intermediate D). High vacuum drying at 60° C. gave the title compound (72 mg, 57%): HPLC MS RT=1.22 min, MH+=512.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.26-2.31 (2H, m), 2.82 (3H, s), 3.11-3.21 (4H, m), 3.45-3.50 (4H, m), 3.83-3.87 (2H, m), 4.27-4.34 (2H, m), 4.42 (2H, t), 4.58-4.65 (2H, m), 7.60 (1H, t), 7.73 (1H, d), 7.85 (1H, d), 7.94 (1H, dd), 8.86 (1H, d), 9.00 (1H, dd), 9.48 (1H, d).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=O)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:25]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]=2[CH:22]([CH3:23])[CH3:24])=[O:27])=[CH:35][CH:34]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)cc3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 80 mg, 0.22 mmol) in CH2Cl2 (5 ml) was added EDC (84 mg, 0.42 mmol) and DMAP (40 mg, 0.32 mmol), followed by 4-fluorobenzyl amine (47 mg, 0.32 mmol). The crude material was purified by chromatography on silica gel (0→45% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].[F-].[K+].O>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[N:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example G.1) (0.265 g, 0.41 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.115 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.081) as a light brown solid. Mp 281° C.
Reaction SMILES: C(O)(=O)C.Br[C:6]1[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[NH:14])=[N:8][CH:9]=[CH:10][CH:11]=1.[C:25]1(OB(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][C:13]([NH:12][C:7]1[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)=[NH:14]
Reactant: COc1ccccc1CNC(=N)Nc1ncccc1Br
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1CNC(=N)Nc1ncccc1-c1ccccc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 19 %

Procedure:
The preparation was carried out analogously to Example 56, using 0.200 g (0.506 mmol) N-(3-bromopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine acetate, 0.092 g (0.759 mmol) phenylboric acid, 0.165 g (1.518 mmol) sodium carbonate, and 0.040 g (0.035 mmol) tetrakis-(triphenylphosphine)palladium(0). The mixture was likewise heated in a reaction block at 110° C., first for 21 hr and then for an additional 20 hr, for a total of 41 hr under a nitrogen atmosphere. After appropriate workup and purification via preparative HPLC, 32 mg pure N-(2-methoxybenzyl)-N′-(3-phenylpyridin-2-yl)guanidine was obtained in the form of the acetate salt (base/acetate in a ratio of 1:1.2).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32OCC[O:24]3)[CH2:6]1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[C:1]([O:4][C@H:5]1[CH:22]=[CH:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23OCCO3)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)O[C@H]1C=C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
Ketal 5 (0.44 g) from Example 1 was dissolved in acetone-water (30 ml, 8:2), and treated with toluene-p-sulfonic acid monohydrate (0.1 g). After the mixture had been stirred at room temperature for 16 hr it was concentrated to half of its volume and diluted with a cold half saturated sodium bicarbonate solution. The solution was cooled, filtered to give white solid compound (0.38 g, 98%), which was further crystallized from methanol. M.p. 185-87° C., purity 99% (LC-MS).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:21])([CH3:20])[CH2:11][C:12](O)([C:15]([F:18])([F:17])[F:16])[CH:13]=O.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-]>>[CH3:20][C:10]1([CH3:21])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)[CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:11]1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Product: COc1cc(C)cc2c1C(C)(C)CC(C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12
Yield: 6.1 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 280 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 156 mg of 5-aminoquinolin-2(1H)-one. The latter is stirred at room temperature with 93 mg of aluminum chloride for 2.5 hours. The batch is added to saturated bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with water and brine, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel (dichloromethane/2-propanol 0->5%), 24 mg of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH:22]=O)[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:22]([C@H:19]1[CH2:20][CH2:21][C@H:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH2:17][CH2:18]1)=[CH2:24]
Reactant: O=C[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Reactant: COC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C[C@H]1CC[C@H](C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.73 g of potassium t-butylate was added to a suspension of 2.3 g of methyltriphenylphosphonium bromide in 25 ml of t-butyl methyl ether in a nitrogen atmosphere and the mixture was stirred at room temperature for 0.5 hour. Then, a solution of 0.8 g of trans-4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanecarboxaldehyde in 25 ml of t-butyl methyl ether was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for a further 0.5 hour and at room temperature for 2.5 hours, thereafter washed with 50 ml of saturated sodium hydrogen carbonate solution and with 50 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was chromatographed on silica gel with hexane. The 4-[(trans-4-vinylcyclohexyl)ethynyl]-4'-fluorobiphenyl obtained was purified by recrystallization from hexane; m.p. (C-N) 133.9° C., cI.p. (N-I) 170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-].CCOCC>ClCCl>[CH3:10][O:9][C:5]1[C:4]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc(OC)c1CCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(C)=O)c(OC)c1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 15.28 g (59.6 mmol) of 1,3-dimethoxy-2-(3-phenylpropyl)benzene from the preceding example, and 4.68 g (59.6 mmol) of acetyl chloride, in 306 mL of dichloromethane was stirred at -5° to 0° C. and 7.95 g (59.6 mmol) of aluminum chloride was added. The resulting mixture was stirred at -5° to 0° C. for 2 hr and then allowed to warm to room temperature before being poured onto ice. Work-up with ether in the usual manner gave a product which was chromatographed on silica gel. Elution with 7:3 hexane-ether afforded 10.0 g (56.3%) of the title compound as a pale-yellow oil.