Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:25][O:26]C(=O)C1C=CC(OC)=CC=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[ClH:39]>CO.O>[ClH:39].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:25][OH:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Nc1ccc(O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(=O)c1cnc2c(CO)cccc2c1Nc1ccc(O)cc1C
Yield: 62 %

Procedure:
A solution of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)quinoline (2.34 g, 4.8 mmol) and sodium hydroxide (0.38 g, 9.6 mmol) in methanol (50 ml) was heated at reflux for 30 minutes, then diluted with water and neutralised with dilute hydrochloric acid. The solid was filtered off and washed with water, then converted to the hydrochloride. Recrystallisation from aqueous ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(hydroxymethyl)quinoline hydrochloride (1.16 g, 62%), m.p. 167°-171°.
Reaction SMILES: Cl.[NH:2]1[CH2:23][CH2:22][CH2:21][C@H:3]1[C:4]([NH:6][C@H:7]([C:18]([OH:20])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5].[N:24]1([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30](O)=[O:31]>CN(C=O)C.CC(O)=O>[N:24]1([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C:30]([N:2]1[CH2:23][CH2:22][CH2:21][C@H:3]1[C:4]([NH:6][C@H:7]([C:18]([OH:20])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5])=[O:31]
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O)N[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Yield: 53.4 %

Procedure:
After 2.25 g (5.0 mmols) of HCl.H-Pro-Arg(NO2)-CHA was dissolved in 10 ml (15.0 mmols) of 1.5N NEM/DMF, 1.93 g (5.0 mmols) of Z-PyroGlu-SDP was added to the solution at 0° to 5° C. The resulting mixture was reacted at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with 300 ml of AcOH followed by washing 4 times with 100 ml of cold 5% hydrochloric acid and twice with 100 ml of saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate and decoloring with activated charcoal, the AcOEt phase was distilled under reduced pressure. The residue was recrystallized from MeOH/AcOEt/ether to give 1.86 g (53.4%) of Z-PyroGlu-Pro-Arg(NO2)-CHA.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:29][C:13]2=[CH:14][C:15]3[C:16](=[O:28])[N:17]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl.[F:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([F:39])=[C:34]([F:40])[C:33]=1[CH2:41][C@@H:42]([NH2:44])[CH3:43].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(O)CCC>[O:8]=[C:4]1[C:3]([C:10]2[NH:11][C:12]3=[CH:20][C:19]4[C:18](=[O:21])[N:17]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)[C:16](=[O:28])[C:15]=4[CH:14]=[C:13]3[N:29]=2)=[C:2]([NH:44][C@@H:42]([CH3:43])[CH2:41][C:33]2[C:34]([F:40])=[C:35]([F:39])[CH:36]=[C:37]([F:38])[C:32]=2[F:31])[CH:7]=[CH:6][NH:5]1
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(c1cccnc1)C3=O
Reactant: C[C@H](N)Cc1c(F)c(F)cc(F)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(c1cccnc1)C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
2-(4-Chloro-2-methoxypyridin-3-yl)-6-(pyridine-3-yl)imidazo[4,5-f]isoindole-5,7(1H, 6H)-dione (0.60 g, 1.48 mmol) was dissolved in 10 mL of 1,4-dioxane and 5 mL of concentrated HCl at rt. The reaction mixture was stirred at rt overnight. Then, the volatile was removed to give a yellow-brown solid. This solid was mixed with (S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.46 g, 2.22 mmol), N,N-diisopropylethylamine (1.32 mL, 7.40 mmol) and n-butanol (30 mL) in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Then, volatiles were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow-brown solid product, 0.65 g, 78.3% yield. MS: 560.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.48 (s, 1H), 11.35 (d, 1H, J=4.5 Hz), 10.91 (d, 1H, J=8.0 Hz), 8.73-8.72 (m, 1H), 8.63-8.61 (m, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.95 (dd, 1H, J=8.0 Hz, J2=2.0 Hz), 7.77-7.70 (m, 1H), 7.62-7.58 (m, 1H), 7.41 (t, 1H, J=4.5 Hz), 6.18 (d, 1H, J=7.5 Hz), 4.25 (m, 1H), 3.18-3.10 (m, 2H), 1.93 (d, 3H, J=6.0 Hz).
Reaction SMILES: [OH-:1].[K+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][N:15]=[CH:14][C:13]=3[C:12]=2[C:20]#[N:21])[CH2:5][CH2:4]1>C(O)(C)(C)C.C(O)C>[NH:3]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][N:15]=[CH:14][C:13]=3[C:12]=2[C:20]([NH2:21])=[O:1])[CH2:5][CH2:4]1
Reactant: [OH-]
Reactant: N#Cc1c(OC2CCCNCC2)ccc2[nH]ncc12
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Product: NC(=O)c1c(OC2CCCNCC2)ccc2[nH]ncc12
Reaction time: 30 h
Yield: 25.3 %

Procedure:
Potassium hydroxide (powder, 100 mg) was added to a solution of the 5-(azepan-4-yloxy)-1H-indazole-4-carbonitrile (9.2 mg, 0.036 mmol) obtained in Example 691 in t-butanol (2 ml) at room temperature, and the resulting mixture was stirred for 30 hours with heating under reflux while maintaining the temperature. The reaction mixture was diluted with ethanol and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol/28% aqueous ammonia) to obtain 5-(azepan-4-yloxy)-1H-indazole-4-carboxamide (2.5 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([NH:10][NH2:11])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Clc1nccnc1Cl
Solvent: O
Solvent: CCO
Product: Cl
Product: NNc1nccnc1Cl
Reaction time: 72 h

Procedure:
A solution of 2,3-dichloropyrazine (3.822 g, 25.65 mmol) in absolute ethanol (20 mL) was treated with hydrazine hydrate (2.74 mL) at room temperature. The mixture was stirred for 3 days then filtered and washed with ethanol (20 mL) to yield 2-chloro-3-hydrazinylpyrazine hydrochloride as an off-white fluffy solid (4.04 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(OC([N:17]=[C:18]=S)=O)C.O.[NH2:21]O>C1(C)C=CC=CC=1>[NH2:21][C:18]1[N:1]=[C:2]2[N:3]([C:4]([O:10][CH3:11])=[N:5][CH:6]=[C:7]2[O:8][CH3:9])[N:17]=1
Reactant: COc1ncc(OC)c(N)n1
Reactant: CCOC(=O)N=C=S
Reactant: NO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 87 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a 700 mL jacketed vessel equipped with a mechanical stirrer, a dual pH/temperature probe, a nitrogen inlet, and a reflux condenser was added sequentially 27.9 g (0.180 mol) of 4-amino-2,5-dimethoxypyrimidine followed by 165.4 g (0.207 mol) of 16.4 wt % ethoxy carbonylisothiocyanate solution in toluene. The reaction mixture was heated to gentle reflux (87° C.) for 7 h at which time liquid chromatographic (LC) analysis indicated ˜95% conversion of starting 4-amino-2,5-dimethoxypyrimidine. The reaction mixture was cooled to 27° C. and allowed to stand overnight. The mixture was heated to 40° C. and then 114.2 g (6.34 mol) of deionized water was added to the mixture. After heating to reflux (˜68° C.), 14.3 g (0.217 mol) of a 50 wt % aqueous hydroxylamine solution was continuously added over a 2 h 15 min period via a peristaltic pump. During the course of the amine addition, the reaction pH rose from 4.44 to 6.95. After complete addition of hydroxylamine, the pump line was flushed with 4.8 g (0.266 mol) of deionized water, the reaction mixture was heated to 81° C., and then stirred an additional 3 h during which time the reaction pH naturally raised to 7.40. The reaction mixture was cooled to ambient temperature (26° C.). The reaction mixture was then suction transferred into a temporary holding vessel. The reactor was washed with two 30 g portions of water. These water washes were combined with the reaction mixture. The combined mixture was suctioned filtered through a coarse Buchner funnel (filtration time about 30 seconds), and the filtrate was collected and filtered a second time through the cake. A final displacement cake wash with ˜40 g of methanol was performed and the product was dried at 60° C. under vacuum (˜<10 mm Hg; 1333 Pa) to afford 25.37 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine as a light cream colored solid. NMR analysis (using benzyl acetate as an internal standard) indicated an 97.3% purity of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine active which corresponds to a 70.4% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:33]=[C:15]3[N:16]=[C:17]([N:27]4[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]4)[CH:18]=[C:19]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:14]3[N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C.O>ClCCl>[CH3:34][S:35]([O:32][C@H:29]1[CH2:30][CH2:31][N:27]([C:17]2[CH:18]=[C:19]([NH:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:14]3[N:13]=[C:12]([C:3]4[C:2]([CH3:1])=[N:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH:33]=[C:15]3[N:16]=2)[CH2:28]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(N3CCC(O)C3)cc(NC3CCOCC3)n2n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc2ccccc2nc1-c1cc2nc(N3CC[C@H](OS(C)(=O)=O)C3)cc(NC3CCOCC3)n2n1
Reaction time: 2 h

Procedure:
To a solution of 1-[2-(3-methylquinoxalin-2-yl)-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-3-ol (200 mg, 0.449 mmol) and methanesulfonyl chloride (77 mg, 0.673 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.125 mL, 0.898 mmol) at 0° C. After being stirred for 2 h, the reaction mixture was poured into water. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=97:3) to give (3S)-1-[2-(3-methylquinoxalin-2-yl)-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-3-yl methanesulfonate (the compound of Example 1.008 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.73-1.83 (2H, m), 2.12-2.15 (2H, m), 2.30-2.39 (1H, m), 2.47-2.52 (1H, m), 3.04 (3H, s), 3.08 (3H, s), 3.56-3.63 (2H, m), 3.68-3.89 (4H, m), 3.99-4.02 (1H, m), 4.07-4.10 (2H, m), 5.19 (1H, s), 5.44-5.46 (1H, m), 6.20 (1H, d, J=8.2 Hz), 6.67 (1H, s), 7.70-7.77 (2H, m), 8.03-8.06 (1H, m), 8.16-8.19 (1H, m).
Reaction SMILES: [CH2:1](/[C:4](=[CH:8]\[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])/[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].F[B-](F)(F)F.[H][H]>CO>[C:12]1([S:9]([CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:7])=[O:6])(=[O:11])=[O:10])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: CCC/C(=C\S(=O)(=O)c1ccccc1)C(=O)O
Agent: F[B-](F)(F)F
Solvent: CO
Product: CCCC(CS(=O)(=O)c1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 102.5 %

Procedure:
(E)-2-Propyl-3-phenylsulfonylacrylic acid (0.3 g, 1.18 mmol) was dissolved in degassed methanol (15 ml) and [(S,S)-EtDuPHOS Rh (COD)]BF4 (8 mg, 1.18×10−2 mmol) was added under a stream of nitrogen. This solution was injected into the pressure vessel under nitrogen, and then the bomb was charged with hydrogen. The mixture was hydrogenated at 2070 kPa (300 psi) for 3 hour at room temperature. The methanol was removed under reduced pressure to give the title compound (0.31 g, 100% yield). E.e. was determined by chiral HPLC to be 92% e.e. [Chiropak AD; 5% ethanol-95% heptane; 1 ml/min; 254 nm; major enantiomer Rf 18.46 min., minor enantiomer Rf 15.22 min.]
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@@H:30]([CH3:65])[C@@H:31]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:32]([NH:34][NH:35][C:36](=[O:53])[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@@H:30]([CH3:65])[C@@H:31]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[C:57]([Cl:63])[C:56]=1[CH3:64])[C:32]1[O:53][C:36]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[CH:41][CH:42]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23]
Reactant: COc1ccc(COc2ccc(C(=O)NNC(=O)[C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(COc2ccc(-c3nnc([C@H](Nc4ccc(C#N)c(Cl)c4C)[C@H](C)O[Si](C)(C)C(C)(C)C)o3)cc2)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Polymer supported Triphenylphosphine (3 g, 8.38 mmol) was dissolved in 250 mL of DCM followed by addition of I2 (2.13 g, 8.38 mmol) and TEA (3.11 mL, 22.36 mmol) at 0° C. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-(4-methoxybenzyloxy)benzohydrazide (3.56 g, 5.59 mmol) in 200 ml DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to warm to room temperature and stirred for additional 10 minutes. The reaction was quenched with 50 ml saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3×80 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO2) to provide the title compound (3.02 g, 87%). 1H NMR (400 MHz, Acetone d6, δ in ppm): 7.93 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 1H), 7.43 (d, J=9 Hz, 2 H), 7.18 (d, J=9 Hz, 2 H), 6.96 (d, J=9 Hz, 2 H), 6.83 (d, J=9 Hz, 1H) 5.52 (d, J=9 Hz, 1 H), 5.21 (dd, J=2 and 9 Hz, 1 H), 5.13 (s, 2H), 4.73 (m, 1 H), 3.80 (s, 3 H), 2.41 (s, 3H), 1.47 (d, J=6 Hz, 3 H), 0.86 (s, 9 H), 0.11 (s, 3 H), 0.01 (s, 3 H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O:15][C:16](=[O:18])[CH3:17])(=O)C.S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>[O-2].[O-2].[O-2].[Cr+6]>[C:24]([O:27][CH:11]([O:15][C:16](=[O:18])[CH3:17])[C:1]1[CH:2]=[CH:3][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:5][CH:6]=1)(=[O:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CC(=O)OC(OC(C)=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution of p-toluenesulfonyl chloride (40.2 g) in acetic acid:acetic anhydride (800 mL, 1:1) was treated with conc. sulfuric acid (64 mL, 5 equivalents) at 0-5° C. Chromium trioxide (80 g, 4 equivalents) was added at such a rate that the temperature remained below 10° C. The mixture was stirred at 5-10° C. until reaction was completed as indicated by TLC. The mixture was quenched with ice water (2 L), and the solids were filtered, washed with water, and dried. The solids were combined with saturated NaHCO3 (1 L) at 25° C. for 2 hrs, filtered, dissolved in dichloromethane (1 L), dried over Na2SO4, filtered and concentrated. The residue was recrystallized from 2-3 volumes of hot acetone/pentane and cooling for 16 hrs. The crystals are filtered, and washed with cold pentane to give the product (24 g, 38%). 1H NMR (CDCl3): δ 8.09 (d, J=9 Hz, 2H), 7.77 (d, J=9 Hz, 2H), 7.73 (s, 1H), 2.16 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[CH3:10][NH:11][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN
Product: CNc1ccc(C#N)cn1
Temperature: 80 °C

Procedure:
Four batches of 6-chloro-3-pyridinecarbonitrile (0.40 g, 2.89 mmol) in methylamine (16 mL, 2M solution in THF) were each heated at 80° C. for 30 minutes in a microwave reactor. The reaction mixtures were combined and concentrated in vacuo. The residue was re-dissolved in EtOAc/water and the organic layer was separated, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography; elution with EtOAc/petroleum ether gave the title compound as a white solid (1.46 g). δH (CDCl3, 400 MHz) 8.37 (1H, d), 7.59 (1H, dd), 6.39 (1H, dd), 5.19 (1H, br.s), 2.99 (3H, d). MS (ES): MH+ 134.2.
Reaction SMILES: [CH:1]1([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrCBr.C1(=O)CCCCCCCCCCCC1>[Ti](Cl)(Cl)(Cl)Cl.[Zn].O1CCCC1>[CH2:14]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=CC1CCCCCCCCCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C1CCCCCCCCCCCC1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCBr
Product: C=C1CCCCCCCCCCCC1

Procedure:
The cyclotridecanecarbaldehyde listed above is also a novel compound which is prepared in the following manner: Titanium tetrachloride is added to a mixture of zinc dust, anhydrous tetrahydrofuran and dibromomethane. To the resulting mixture is added cyclotridecanone to yield methylene cyclotridecane which is then epoxidized with m-chloroperbenzoic acid. After purification, the epoxidized product is reacted with boron trifluoride-ether complex in anhydrous dichloromethane to yield cyclotridecanecarbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2(O)[CH2:11][O:10][CH2:9]2)[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1.COCCN(S(F)(F)[F:33])CCOC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([F:33])[CH2:11][O:10][CH2:9]2)[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1
Reactant: COC(=O)c1csc(-c2c(F)cc(C3(O)COC3)cc2F)n1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(-c2c(F)cc(C3(F)COC3)cc2F)n1
Temperature: 25 °C

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (see US2012/225062) gave the title compound, after adding the following fluorination step prior to ester hydrolysis: A solution of methyl 2-(2,6-difluoro-4-(3-hydroxyoxetan-3-yl)phenyl)thiazole-4-carboxylate (50 mg) in dichloromethane (5 mL) was cooled to −78° C., then deoxo-fluor (1.5 equiv., 50 wt % solution in toluene) was added. The mixture was allowed to slowly warm to rt over 30 minutes. The reaction was then quenched by the addition of sat. NaHCO3(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by CombiFlash (0 to 100% EtOAc in heptane) provided methyl 2-(2,6-difluoro-4-(3-fluorooxetan-3-yl)phenyl)thiazole-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:24]1>>[OH:7][C:3]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[C:4]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:24]1[NH:23][C:31]2[C:26]([C:25]=1[CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: CC(=O)NCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Product: CC(=O)NCc1c(C(C2=C(O)C(C)(c3ccc(C)cc3)C2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and N-(1H-indol-3-ylmethyl)-acetamide (Lit. 6) to give the title compound as an off-white solid. MS: 463.4 ([M−H]−).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[S:9].[Br:10][CH:11]([CH3:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>CC(C)=O>[BrH:10].[CH3:20][CH:11]1[S:9][C:2]2=[N:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:1]2[C:12]1([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: S=C1NCCCCCN1
Solvent: CC(C)=O
Product: Br
Product: CC1SC2=NCCCCCN2C1(O)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 1.44 g. of hexahydro-1,3-diazocine-2(1H)-thione and 500 ml. of acetone is heated to produce solution. A 2.13 g. portion of 2-bromopropiophenone is added and the mixture is allowed to stand overnight. The solid is collected, washed with acetone and dried, giving 2.53 g. of the desired product, m.p. 191°-193° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44].O>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:30][CH:31]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCCCBr
Reactant: Oc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCCCOc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
The obtained 3,6-diphenyl-9-(4-hydroxyphenyl)carbazole (1.54 g, 3.7 mmol) was dissolved in N,N-dimethylformamide (20 mL). Under cooling with ice water, 55% by mass sodium hydride (0.25 g, 5.7 mmol) was added to the resultant solution, followed by stirring for 1 hour. Next, 8-bromo-1-octanol (1.16 g, 5.5 mmol) was added thereto, and the resultant mixture was stirred for 3 hours at room temperature. In addition, the mixture was poured to water, followed by extraction with ethyl acetate. Next, the mixture was washed with water and dried and the solvent was evaporated, to thereby obtain 1.90 g of 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octan-1-ol.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH2:19]([C:22]1([CH:29]=[O:30])[CH2:27][CH:26]2[CH2:28][CH:23]1[CH:24]=[CH:25]2)[CH:20]=[CH2:21]>CCCCCC.C1COCC1>[CH2:19]([C:22]1([CH:29]([OH:30])[CH:10]([C:9]2[CH:16]=[CH:17][CH:18]=[C:7]([Cl:6])[CH:8]=2)[N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:27][CH:26]2[CH2:28][CH:23]1[CH:24]=[CH:25]2)[CH:20]=[CH2:21]
Reactant: C=CCC1(C=O)CC2C=CC1C2
Reactant: Clc1cccc(Cn2ccnc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC1(C(O)C(c2cccc(Cl)c2)n2ccnc2)CC2C=CC1C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
13.8 ml (20 mmol) of a 1.45 molar solution of n-butyllithium in hexane were added dropwise to a solution of 3.85 g (20 mmol) of 1-(3-chlorobenzyl)-imidazole in 40 ml of absolute THF at -70° C. After stirring for 30 minutes at -70° C., a solution of 4.39 g of 74% purity (20 mmol) 2-allyl-5-norbornen-2-aldehyde in 30 ml of absolute THF was added dropwise at about -70° C. over about 12 minutes. The further procedure was subsequently carried out as described in Example 2. The residue (9.0 g) remaining from the organic component after removing the solvent by distillation was dissolved in diisopropyl ether/hexane 2:1, whereupon crystalline product precipitated. After isolation using 20 ml of acetonitrile, this was boiled briefly, filtered off under suction after cooling the mixture, and washed with acetonitrile. 2.70 g (≅38% yield) of pure 1-(2-allyl-5-norbornen-2-yl)-2-(3-chlorophenyl)-2-(1-imidazolyl)-ethanol were obtained in the form of a mixture, comprising 2 diastereomers, of melting point 134°-135° C.