Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[C:10]([CH3:26])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:12](N)=[N:13][CH:14]=1.[ClH:27]>CC#N.[Cu](Cl)Cl>[Br:8][C:9]1[C:10]([CH3:26])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:12]([Cl:27])=[N:13][CH:14]=1
Reactant: Cl
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1c(Br)cnc(Cl)c1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
To a suspension of copper (II) chloride (421 mg, 3.92 mmol) and t-butyl nitrite (466 μL, 3.92 mmol) in dry MeCN (12 mL) at 70° C. was added 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 864 mg, 2.61 mmol) dropwise as a solution in MeCN (3 mL) over 5 mins. The reaction mixture was stirred at 70° C. for 3.5 hrs then poured onto 5 N aqueous HCl (20 mL). The reaction mixture was extracted with EtOAc (4×20 mL) then the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as an orange solid (184 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:12][C@H:11]([CH2:13][O:14][Si](C(C(C)C)(C)C)(C)C)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([NH:8][C@H:9]1[CH2:12][C@H:11]([CH2:13][OH:14])[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)C(C)(C)[Si](C)(C)OC[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](CO)C1

Procedure:
Analogously to Example 6b, starting from a solution of 13.2 g (0.03842 mol) of trans3-(N-BOC-amino)-1-(thexyl-dimethylsilyl)oxymethyl-cyclobutane (cf. Example 6c) in 60 ml of tetrahydrofuran and 76.8 ml (0.0768 mol) of a 1M tetrabutylammonium fluoride solution in tetrahydrofuran, the title compound is obtained, m.p. 98°-100° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Cl[CH2:20][C:21]1[N:22]=[C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]2[CH:30]=1>C1COCC1>[CH3:29][C:28]1[C:23]2[N:24]([CH:30]=[C:21]([CH2:20][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccn2cc(CCl)nc12
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccn2cc(CCC#C[Si](C)(C)C)nc12
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of trimethyl(prop-1-ynyl)silane (259 mg, 2.31 mmol) in THF (7.5 mL) at −78° C. was added n-BuLi 2.5M in hexane (1.1 mL, 2.8 mmol). After 90 min at −78° C. 2-(chloromethyl)-8-methyl-imidazo[1,2-a]pyridine (500 mg, 2.8 mmol) in THF (5 mL) was added dropwise. The solution became blue-green at −78° C. The solution was stirred at −78° C. for an additional 1 h. The reaction was quenched with water and the solvent was removed under reduced pressure. The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent) to afford 590 mg of 8-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 100%) as an yellow oil.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=O)[CH:14]=2)[CH2:9]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:6][NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN[C@H]1CCc2cc(CN3CCCC3)ccc2C1

Procedure:
According to method B, [(S)-6-(pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]carbamic acid tert-butyl ester was reacted with lithium aluminum hydride (10 equiv., 60° C., 2 hours). The product was thus obtained with the molecular weight of 244.38 (C16H24N2); MS (ESI): 245 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][CH:11]=[CH:12][C:3]=12.[CH:13]([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.IC>O1CCCC1.O.ClCCl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][C:11]([CH3:13])=[CH:12][C:3]=12
Reactant: N#Cc1cnc2sccc2c1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(Cl)c(C#N)cnc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (0.3 g, 1.54 mmol) in 15 mL of tetrahydrofuran at −78° C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (0.93 mL, 1.85 mmol). After stirring for 45 min, a solution of iodomethane (0.115 mL, 1.85 mmol) in 1 mL of tetrahydrofuran is added dropwise. The reaction mixture is stirred at −78° C. for 4 hours, then dichloromethane and water are added. The mixture is allowed to warm to room temperature, then partitioned between water and dichloromethane. The organic layer is washed with a solution of sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:9 ethyl acetate:hexane to provide 0.1 g of 4-chloro-2-methylthieno[2,3-b]pyridine-5-carbonitrile as colorless crystals, mp 101–102° C.; 1H NMR (DMSO-d6) δ 2.68 (s, 3H), 7.39 (s, 1H), 8.92 (s, 1H); MS 209.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:20](O)=[O:21])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:5][CH:4]=1.[OH:25][CH:26]1[CH2:29][N:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:27]1>>[OH:25][CH:26]1[CH2:29][N:28]([C:30]2[N:31]=[CH:32][C:33]([NH:36][C:20]([C:8]3[N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[C:10]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([C:2]([F:23])([F:1])[F:24])[CH:11]=4)=[O:21])=[CH:34][CH:35]=2)[CH2:27]1
Reactant: Nc1ccc(N2CC(O)C2)nc1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(N2CC(O)C2)nc1)c1cc2ccc(C(F)(F)F)cc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in example 2, using 6-trifluoromethyl-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid and 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, prepared in step 10.2 of example 10 (Compound Ve).
Reaction SMILES: C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:19]12([OH:29])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.[C:30](O)(=[O:34])[C:31]([CH3:33])=[CH2:32]>O>[C:30]([O:29][C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OC12CC3CC(CC(C3)C1)C2

Procedure:
200 ml of toluene and 1 g of p-toluenesulfonic acid were added to 70 g of 1-adamantanol and 50 g of methacrylic acid. They were subjected to a reaction with heating and stirring, while water was distilled off using a Dean-Stark trap. The resulting organic phase was washed with water, a 10 mass % aqueous sodium hydrogencarbonate solution and water in this order and distilled to obtain crude 1-adamantyl methacrylate (a crude product) having a purity of 91 mass %.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:15]=1Br)=[O:10].[C:23]([O:27][C:28]([N:30]1[CH2:35][C:34](=[O:36])[NH:33][C@H:32]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].O1CCOCC1>CCOC(C)=O.[Cu]I>[C:23]([O:27][C:28]([N:30]1[CH2:35][C:34](=[O:36])[N:33]([C:15]2[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][C:11]=2[C:9]([O:8][CH3:7])=[O:10])[C@H:32]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N[C@H](C2CCCCC2)C1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CN(C(=O)OC(C)(C)C)C[C@H]1C1CCCCC1
Temperature: 110 °C
Yield: 29.4 %

Procedure:
A tube was charged with trans-cyclohexanediamine (162 mg, 1.42 mmol, 0.5 equiv), K2CO3 (783 mg, 5.67 mmol, 2.0 equiv), 3-bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.01 g, 3.40 mmol, 1.2 equiv), CuI (270 mg, 1.42 mmol, 0.5 equiv), (R)-3-Cyclohexyl-5-oxo-piperazine-1-carboxylic acid tert-butyl ester (800 mg, 2.83 mmol, 1.0 equiv) and 1,4-dioxane (3.0 mL). The tube was then flushed with N2 and sealed. The reaction mixtures were heated at 110° C. for 72 hours after which it was diluted with EtOAc and filtered. The filtrate was washed with 1.0 N HCl aq. solution, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane, 50%) to give product (R)-3-Cyclohexyl-4-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-5-oxo-piperazine-1-carboxylic acid tert-butyl ester 415 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1)[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[N:21]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([O:19][CH3:18])[N:21]=[C:22]([NH:28][C:29]([NH:17][S:14]([C:10]2[N:8]3[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]3=[N:12][C:11]=2[CH3:13])(=[O:15])=[O:16])=[O:30])[N:23]=1
Reactant: CCOc1ccc2nc(C)c(S(N)(=O)=O)n2c1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1ccc2nc(C)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
As shown in the above reaction scheme, 6-ethoxy-2-methylimidazo[1,2-a]pyridin-3-sulfonamide (0.04 g, 0.156 mmol) and phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.048 g, 0.172 mmol) were suspended in acetonitrile (1 ml) and stirred at room temperature, during which DBU (0.026 g, 0.172 mmol) was added thereto. After the mixture was stirred at room temperature for 2 hours, the reaction solution was poured into water (20 ml) and adjusted to pH 3 with dilute hydrochloric acid. The precipitated crystals were collected by filtration, and washed with water and ether in this order. The crystals were dried under reduced pressure to give the title compound as pale brown crystals. The yield was 0.06 g (87%), and the melting point was 159 to 164° C. (dec.).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)=CC=1)([O-])=O.[Li+].[OH-]>C1COCC1>[OH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18](=[O:19])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.8 %

Procedure:
To a stirred solution of (1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl 4-nitrobenzoate (1.95 g, 5.35 mmol) in THF (50 mL) was added a solution of 1N LiOH (9.63 mL, 9.63 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours and then partitioned between EtOAc and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (EtOAc/hexane, 1:1) to give tert-butyl (1S,2R)-2-hydroxycyclohexylcarbamate (1.15 g, 100%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:13])[N:6]([CH2:11][CH3:12])[N:7]=2)[CH:3]=1.[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][N:24]([C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[C:5]([CH3:13])[N:6]([CH2:11][CH3:12])[N:7]=4)[CH:3]=3)[C:23](=[O:27])[CH:22]=2)=[CH:17][CH:16]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: CCn1nc2ccc(Br)cc2c1C
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCn1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2c1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 13.6 %

Procedure:
To a solution of 5-bromo-2-ethyl-3-methyl-2H-indazole (200 mg), 4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one (158 mg) and potassium carbonate (347 mg) in 1,4-dioxane (10 ml) were added copper(I) iodide (64 mg) and trans-N,N′-dimethylcyclohexane-1,2-diamine (47 mg), and the mixture was stirred at 110° C. for 16 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue were added dichloromethane and water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (36 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:32][C:33]1[S:37][C:36]([CH:38]=[CH:39][S:40](Cl)(=[O:42])=[O:41])=[CH:35][CH:34]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([S:40]([CH:39]=[CH:38][C:36]2[S:37][C:33]([Cl:32])=[CH:34][CH:35]=2)(=[O:42])=[O:41])[CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(CN2CCN(S(=O)(=O)C=Cc3ccc(Cl)s3)CC2=O)cc2cnccc21
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxopiperazin-1-ylmethyl)pyrrolo[3,2-c]pyridin-1-carboxylic acid tert-butyl ester (0.71 g, 2.1 mmol), EXAMPLE 69, in CH3CN (7 mL) is added triethylamine (0.60 mL, 4.3 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride, EXAMPLE 3, (0.57 g, 2.1 mmol). The mixture is stirred overnight, then concentrated to dryness. The residue is diluted with CH2Cl2 and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.2 g, 2.1 mmol) as a light yellow solid. The crude material can be used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.80 (s, 1H), 8.42 (d, 1H), 7.88 (d, 1H), 7.55 (d, 1H), 7.14 (d, 1H), 6.98 (d, 1H), 6.41 (s, 1H), 6.36 (d, 1H), 5.00 (s, 2H), 3.98 (s, 2H), 3.61 (m, 4H), 1.71 (s, 9H). Ion spray MS, [M+H]+=537, 539, Cl pattern.
Reaction SMILES: C([S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(C)(C)C.O.C(SC1C=CC(N)=CC=1)(C)(C)C.[C:28](Cl)(Cl)=[O:29]>[Fe].C1C=CC=CC=1.C(O)(=O)C>[SH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:28]=[O:29])=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)Sc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: CC(C)(C)Sc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C=Nc1ccc(S)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(t-butylmercapto)nitrobenzene (52.8 g., 0.25 mol) and iron powder (150 g.) in 1 l. of water there was added 1 ml. of acetic acid. The reaction mixture was stirred 18 hours at 90°C. and filtered. Both the residue and filtrate were extracted several times with methylene dichloride, and the combined dried methylene dichloride extracts were concentrated at reduced pressure to give 18.2 g. of a brown oil. This is a 40% weight yield of 4-(t-butylmercapto)aniline. To this oil in 100 ml. of benzene there was then added dropwise 158 g. of a 12.5% benzene solution of phosgene (0.2 mol) with cooling. The reaction mixture was stirred for 1 hour at 10°C., overnight at room temperature and then at reflux temperature for 7 hours. After standing overnight the reaction mixture was filtered, the filtrate concentrated at reduced pressure, then vacuum-distilled. Two product fractions were collected as
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][C@H:18]([N:25]1[C:34](=[O:35])[CH2:33][C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][C:26]1=[O:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C@@H:18]([N:25]2[C:34](=[O:35])[CH2:33][C:28]3([CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:27][C:26]2=[O:36])[CH2:17][N:13]2[CH2:12][CH2:11][N:10]([C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:15][CH2:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1[C@@H](CCl)c1ccccc1
Reactant: Fc1cc(F)c(N2CCNCC2)cc1F
Product: O=C1CC2(CCCC2)CC(=O)N1[C@@H](CN1CCN(c2cc(F)c(F)cc2F)CC1)c1ccccc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
A mixture of 1-(2,4,5-trifluorophenyl)piperazine (20 mg, 0.093 mmol) and (R)-8-(2-chloro-1-phenylethyl)-8-azaspiro[4.5]decane-7,9-dione (20 mg, 0.066 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative TLC, giving the title compound as an off-white solid (9.5 mg, 0.020 mmol, 30%): ESI-MS m/z 486 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([CH2:18][C:19]3([CH2:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20]3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[NH2:29][CH2:28][CH2:27][CH2:26][C:19]1([CH2:18][S:15]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH2:10][CH2:11]2)(=[O:16])=[O:17])[NH:20][C:21](=[O:25])[NH:22][C:23]1=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCC1(CS(=O)(=O)N2CCC(Oc3ccc(Cl)cn3)CC2)NC(=O)NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCC1(CS(=O)(=O)N2CCC(Oc3ccc(Cl)cn3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
1,1-dimethylethyl 3-{4-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]-2,5-dioxoimidazolidin-4-yl}propylcarbamate (426 mg, 0.78 mmol) was dissolved in 10 mL CH2Cl2 and 4 mL of TFA was added. The reaction was stirred at rt for 1 hour. The solvent was removed to give 408 mg (93%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[C:35]([O:41][CH3:42])[CH:34]=1>>[CH3:30][O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22](=[O:23])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:3]=2)=[C:35]([O:41][CH3:42])[CH:34]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(OC)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-3-methoxy-benzoic acid methyl ester following the procedure of Example 478: mp 60-63° C.; MS (ES) m/z 571.9; HRMS: calcd for C33H24F3NO5+H+, 572.16793; found (ESI, [M+H]+), 572.1708.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23]([OH:25])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[NH:22][CH:21]=2)=[O:25])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([F:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=1)#[CH:17]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[CH:20][C:21]([F:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Yield: 49.3 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (520 mg, 3.49 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (62 mg, 0.09 mmol), copper(I) iodide (10 mg, 0.05 mmol), and triethylamine (718 mg, 7.10 mmol). After heating the reaction at 60° C. for 30 min, N-(5-ethynyl-2-fluorophenyl)-2,2,2-trifluoroacetamide (410 mg, 1.77 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (5-50% EtOAc in hexanes) to afford the desired product (300 mg, 49%) as an off white solid. ESIMS (M+H)+=344.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][C:16]=2[F:35])=[CH:11][N:10]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][C:16]=2[F:35])=[CH:13][N:14]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2ccc(-c3ccccc3S(N)(=O)=O)cc2F)cn1
Reaction time: 4 h
Yield: 59 %

Procedure:
Trifluoroacetic acid (1 mL) was added to neat 4′-(2-aminopyrimidin-5-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (52 mg, 0.13 mmol). After 4 hours, the resulting solution was concentrated to dryness and purified by HPLC to provide the title compound (33 mg, 59%) as a clear glassy solid. MS (ESI): mass calcd. for C16H13FN4O2S, 344.07; m/z found, 345.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J=1.3, 2H), 8.05 (dd, J=7.8, 1.4, 1H), 7.70-7.56 (m, 3H), 7.40-7.28 (m, 5H), 7.03 (s, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:10]=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=1)(=O)=O.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:7]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=2)=[CH:8][C:9]([C:19]([F:20])([F:21])[F:22])=[N:10]1
Reactant: O=S(=O)(Oc1cc(C(F)(F)F)nn1-c1ccccc1Cl)C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1

Procedure:
1-(2-chlorophenyl)-5-[3-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole was prepared in a manner similar to that described in Examples 1c by using 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl trifluoromethanesulfonate and 3-(methylsulfonyl)phenylboronic acid. 1H-NMR (CDCl3): δ 7.90 (1H, m), 7.76 (1H, d), 7.57-7.47 (3H, m), 7.46-7.42 (3H, m), 6.92 (1H, s), 2.92 (3H, s). MS (ES): 401 [M+H]+.