Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[O:1]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=1)[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: OCCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 3-(2-hydroxyethyl)bromobenzene (4.0 g, 20 mmol) in methylene chloride (100 ml) at 0° C. was added a solution of tert-butyldimethylsilyl chloride (3.6 g, 24 mmol), dimethylaminopyridine (0.61 g, 5 mmol) and triethylamine (3.6 ml, 25.9 mmol). After 1 h, the reaction mixture was washed with brine, saturated ammonium chloride, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 0-10% hexane/ethyl acetate) to give 3-(2-tert-butyl-dimethylsiloxyethyl)bromobenzene (6.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([F:19])[C:13]=4[CH:12]=[C:9]3[C:10]=2[CH:11]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:19][C:14]1[C:13]2[CH:12]=[C:9]3[N:8]([C:18]=2[CH:17]=[CH:16][CH:15]=1)[CH2:7][CH2:6][C:5]1[N:4]=[CH:3][C:2]([C:37]2[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]4[O:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=4[CH:36]=2)=[CH:11][C:10]3=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ncc(Br)cc2-1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 40.8 %

Procedure:
A mixture of 2-bromo-11-fluoro-5,6-dihydroindolo[2,1-f][1,6]naphthyridine (50 mg, 0.16 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (87 mg, 0.17 mmol), potassium carbonate (43 mg, 0.32 mmol) and Pd(dtbpf)Cl2 (10 mg) in 1,4-dioxane/water (1/0.1 mL) was stirred at 100° C. for 6 hours under nitrogen atmosphere. The mixture was filtered through Celite pad and concentrated, and then the residue was diluted with water and EA. After extraction with EA, the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford the desired product (40 mg, yield: 41.7%) through the prep-HPLC. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 8.19 (s, 1H), 7.93˜7.96 (m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.19˜7.24 (m, 2H), 7.15˜7.17 (m, 2H), 7.02 (s, 1H), 6.77˜6.82 (m, 1H), 5.88 (br s, 1H), 4.41˜4.44 (m, 2H), 3.45˜3.49 (m, 2H), 3.18 (s, 3H), 2.99 (d, J=4.80 Hz, 3H), 2.84 (s, 3H). MS (M+H)+: 613.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([OH:18])=[O:17].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:23](=[O:25])[CH3:24])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of N-(3,4-Dichlorobenzyl)-5-hydroxyindole-2-carboxylic acid (10 g) in warm ethyl acetate (250 ml) was added 4-dimethylaminopyridine (100 mg) and acetic anhydride (5.0 ml) and the resulting mixture was stirred for 2 hours. The organics were washed with 1N HCl and dried. Hexane was added to cause crystallision of the product. The solid was filtered and washed with hexane to give the desired product. (5 g, 44%). 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 5.85 (s, 2H), 6.9 (dd, 1H), 7.05 (dd, 1H), 7.3-7.6 (m, 5H); m/z 378, 380 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=O)[CH2:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.S(F)(F)(F)[F:26]>C(Cl)Cl>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:26])=[CH:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FS(F)(F)F
Reactant: O=C1Cc2ccccc2N(Cc2ccccc2)c2ccccc21
Agent: F
Solvent: ClCCl
Product: FC1=Cc2ccccc2N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of 149.7 g (0.5 mole) of 5-benzyl-5,11-dihydro-10H-dibenz[b,f]azepin-10-one (vide British Pat. No. 961 444),27 ml of hydrogen fluoride, 125 g of sulphur tetrafluoride and 400 ml of methylene chloride is heated in a steel autocalve for 16 hours to 70° C. After the mixture has cooled, the bulk of the liquid constituents are filtered off with suction. Then water and aqueous ammonia solution are added until the pH of the aqueous phase is 9-10. The organic phase is separated, washed three times with water, diluted with 200 ml of benzene and concentrated in a rotary evaporator. The black residue is dissolved in methylene chloride and the solution is filtered through 700 g of silica gel (particle size 0.063-0.2 mm) with methylene chloride as eluant. The filtrate is concentrated, the residue dissolved in 1.5 liters of benzene and stirred for 30 minutes with 500 g of magnesium silicate gel. The mixture is filtered and 500 g of magnesium silicate gel are again added to the filtrate. After repeated filtration, the solution is concentrated in vacuo and the black residue is chromatographed over 800 g of silica gel (particle size 0.063-0.2 mm) with hexane/benzene (2:1) as eluant. The homogeneous fractions are combined and concentrated to yield the 5-benzyl-10-fluoro-5H-dibenz[b,f]azepine as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([C:31]([CH3:33])=[CH2:32])[N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]>CO.O1CCCC1.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:34][CH:35]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: C=C(C)c1nccc(N2CCC(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)CC2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nccc(N2CCC(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)CC2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 1115.7 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[1-(2-isopropenylpyrimidin-4-yl)piperidin-4-yl]methyl}benzamide (10 mg) in 1.33 ml of methanol and 0.66 ml of tetrahydrofuran was added 3 mg of 10% palladium on carbon. This mixture was evacuated and flushed with a hydrogen-filled balloon ten times. The reaction mixture was stirred at 50° C. for 1 h, and then at room temperature for 15 h. The mixture was then filtered through a plug of Celite, eluting with methanol. After concentration of the eluent in vacuo, the residue was further purified by filtration through a plug of silica gel, eluting with ethyl acetate. Concentration of the residue in vacuo provided the title compound (112 mg, 93%). Mass spectrum (ESI) 523.4 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8.3 Hz, 2H), 8.16 (d, J=6.2 Hz, 1H), 7.95 (d, J=8.0 Hz, 3H), 7.52 (s, 1H), 6.32 (m, 3H), 4.52 (d, J=9.1 Hz, 2H), 3.46 (m, 3H), 2.97 (sept, J=6.9 Hz, 1H), 2.91 (t, J=11.3 Hz, 2H), 2.00 (s, 1H), 1.88 (d, J=12.1 Hz, 2H), 1.46 (d, J=6.8, 6H), 1.33 (m, 2H), 1.28 (d, J=6.9, 6H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[F:11][C:12]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:15]=[CH:14][C:13]=1[CH2:26][C:27](Cl)=[N:28][OH:29].C(N(CC)CC)C>O1CCCC1>[F:11][C:12]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:15]=[CH:14][C:13]=1[CH2:26][C:27]1[CH:2]=[C:1]([C:3]2[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=2)[O:29][N:28]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1F
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccccn4)cc3F)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (43.2 mg, 0.325 mmol) described in Manufacturing Example 13-1-3 and (2-fluoro-4-(pyridin-2-yloxymethyl)-phenyl)acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Manufacturing Example 204-1-8 was added triethylamine (97.2 μL, 0.697 mmol), which was stirred for 2 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (73 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CCOC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:14]4[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=4[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=3)=[O:9])[CH:3]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a mixture of (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26, 50 mg, 0.159 mmol) and 4-chlorophenylacetic acid (27.2 mg, 0.159 mmol) in pyridine (1 mL) was added HATU (121 mg, 0.31 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 solution, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 7% MeOH in DCM to afford the title compound (28 mg).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:22]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70].CO>C(Cl)Cl>[Br:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]1[C:59]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[CH:60][C:61]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:25]=3)[C:10]3[C:11](=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:9]=3)[C:62]=2[CH:63]=1
Reactant: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Reactant: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOc1cc2c(cc1CCCCCCCCCCCCCCCCBr)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 988 %

Procedure:
In 40 mL of methylene chloride, 5.70 g (10 mmol) of 3,3′,4,4′-tetrakishexyloxybiphenyl and 15.3 g (31 mmol) of 1-(16-bromohexadecyl)-2-hexyloxybenzene were dissolved. Under argon, 10.0 g (62 mmol) of FeCl3 was added to the solution, and the solution was stirred at ambient temperature for three hours. The resulting reaction mixture was put into 800 mL of methanol and filtered to obtain 102 g of a solid. The solid was purified by silica-gel column chromatography to obtain a yellow solid. The yellow solid was recrystallized from ethanol and 8.2 g of a white solid was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:12]>CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH2:12])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: [NH4+]
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cnc2[nH]ccc2c1
Yield: 63 %

Procedure:
5-bromo-1H-pyrrolo[2,3-b]pyridine (6.0 g, 30.45 mmol) in ammonium hydroxide (120 mL) was treated with copper sulphate pentahydrate (1.50 g, 6.09 mmol, 0.2 eq) and heated in a sealed tube overnight. The reaction was diluted with EtOAc and the insoluble black solid was filtered off. The filtrate was extracted (EtOAc/Water) and the organic layer washed with saturated aqueous ammonium chloride, followed by water and brine. The organics were dried over magnesium sulphate, filtered and evaporated to dryness to give the product as a pale brown solid (2.57 g, 63%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.C([Li])CCC.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=2)[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[CH2:13][CH2:14]1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccccc1N1CCN(CCc2ccncc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N1CCN(CC(Cc2ccc(F)cc2)c2ccncc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(2-Methoxyphenyl)-4-[2-(4-pyridyl)ethyl]piperazine (5.94 g, 20 mmol) was dissolved in anhydrous THF (70 ml) and the solution cooled to about -78° C., n-Butyllithium (1.6M solution in hexane, 18 ml) was added in portions, then the mixture was stirred for 1 hour, at below -70° C. The anion was quenched with p-fluorobenzylbromide (3.18 g, 16.8 mmol) in THF (3 ml and the mixture was warmed to room temperature when water (50 ml) was added. The organic component was extracted by dichloromethane, then washed with brine, dried using sodium sulphate and concentrated in vacuo. The resulting oil was purified by column chromatography using methanol:chloroform (0:100-5:95 gradient), affording the pure product. Addition of ethanolic HCl to the oil gave the title compound as the trihydrochloride 1.5 hydrate (1.25 g), m.p. 173°-175° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[S:21].[NH4+].[OH-].O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCCOc1cc(Oc2ccccc2)cnc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(Oc2ccccc2)cnc1NC(N)=S
Reaction time: 19 h
Yield: 81 %

Procedure:
3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-ylamine (0.3 mmol) is dissolved in THF (4 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 19 hours. 32% NH4OH (21 eq.) is added and stirred 3 hours at room temperature. Water (50 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiourea is obtained as brown oil in a yield of 81%; HPLC (method C): 1.85 min; LC-MS (method A): 1.68 min, 320.15 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]#[C:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:19](OC)=[O:20])=[CH:12][CH:11]=1.[NH2:28][OH:29].CC(O)=O>C(O)(C)C>[OH:29][NH:28][C:19](=[O:20])[C:18]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:7]#[C:6][C@@H:4]2[CH2:5][C@H:3]2[CH2:2][OH:1])=[CH:11][CH:12]=1
Reactant: COC(=O)C(C)(CCc1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)S(C)(=O)=O
Reactant: NO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(CCc1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a stirring solution of methyl 4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.7) in isopropanol (1.3 mL) at 0° C. was added hydroxylamine (946 μL, 15.44 mmol, 50% in water) and the reaction was stirred at room temperature overnight. The reaction mixture was neutralized with AcOH (884 μL, 15.44 mmol) and concentrated under reduced pressure to give a crude, which was purified by RP-HPLC (0-30% ACN in water) to yield N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (9, 22.6 mg, 22.6% yield). MS: m/z calcd for C20H23NO5S 389.13. found [M+H]+ 390.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]([CH2:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[C:45](O)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]([CH2:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[C:45]([NH:55][C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A solution of triphenylphosphine (409 mg, 1.56 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (277 mg, 1.56 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid (370 mg, 0.92 mmol) in methylene chloride (5 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (276 mg, 2.76 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/2 hexanes/ethyl acetate) afforded 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-propionamide (83 mg, 18%) as an amorphous solid: EI-HRMS m/e calcd for C20H20ClF3N6OS (M+) 484.1060, found 484.1068.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.[NH2:14][NH2:15]>O>[NH2:1][C:2]1[C:3]([C:9]([NH:14][NH2:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NN
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: O
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 100 °C
Yield: 100.4 %

Procedure:
A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (5 g, 21.55 mmol) and hydrazine hydrate (5.397 g, 5.245 mL, 107.8 mmol) were heated to 100° C. for 1.5 hours. Water was added and the product collected by filtration, washed with methanol and dried to give 3-amino-6-bromo-pyrazine-2-carbohydrazide as a yellow solid (5.02 g, 100.4% Yield). MS (ES+) 233.78
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].Cl>O.C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:15][CH2:16][C:17]1=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
4-Aminobenzoic acid (100 g, 0.73 mol) is suspended in water (400 mL) and toluene (200 mL), and thereto is added dropwise 30% aqueous sodium hydroxide solution (97 g, 0.73 mol) under ice-cooling. After confirming that pH is basic enough, 4-chlorobutyric chloride (103 g, 0.73 mol) and 30% aqueous sodium hydroxide solution (290 g, 2.2 mol) are added dropwise simultaneously while maintaining the pH range of 9-12 and temperature range of 15-20° C. over 1 hour. After stirring at room temperature for 1 hour, sodium hydroxide (88 g, 2.2 mol) is added to the mixture under ice-cooling. To the reaction solution is added conc. hydrochloric acid (370 g) at 30° C. or below and precipitated crystals are collected by filtration. The resulting crystals are washed with water and air-dried at 40° C. to give 4-(2-pyrrolidon-1-yl)benzoic acid (144 g, yield: 96.0%, purity: 98.3%). The purity was determined by HPLC analysis.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]([NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-Bromo-N-tert-butyl-benzenesulfonamide (example B.9) (321 mg, 1.1 mmol) according to general procedure II. Obtained as a light-brown solid (110 mg, 20%). MS (ISP) 567.2 [(M+H)+]; mp 192–200° C.