Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7](C2CCCCO2)[CH:8]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([NH2:31])[C:21]([NH2:30])=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO>[F:17][C:18]1[C:23]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:22][C:21]2[N:30]=[C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=3)[NH:31][C:20]=2[CH:19]=1
Reactant: Nc1cc(F)c(N2CCOCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(N3CCOCC3)c(F)cc2[nH]1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
530 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde (the preparation of which is described in WO 03/035065, reference example 6m page 479) are added slowly to a solution of 500 mg of 4-fluoro-5-morpholin-4-ylbenzene-1,2-diamine in 50 mL of methanol, and then 19.5 mg of ferric chloride are added. The reaction medium is stirred at 22° C. for 18 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-90 cartridge. The elution is carried out as follows: 100% cyclohexane for 20 minutes, then 20 minutes with an 80:20 cyclohexane/ethyl acetate mixture and 120 minutes with a 20:80 cyclohexane/ethyl acetate mixture. 457 mg of 6-fluoro-5-morpholin-4-yl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazoleare isolated. 1H NMR (400 MHz, (CD3)2SO, δ in ppm): 1.42-1.80 (m: 3H); 1.91-2.06 (m: 2H); 2.18 (m: 1H); 3.02 (m: 4H); 3.70 (m: 1H); 3.78 (m: 4H); 4.00 (broad d J=10 Hz: 1H); 5.60 (dd, J=10 and 2 Hz: 1H); 7.18 (very broad s: 1H); 7.45 (very broad s: 1H); 9.18 (s: 1H); 12.85 (very broad s: 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[C:4]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:3]=1.C(O)C.CN>O>[NH2:11][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: O
Solvent: CCO
Product: NCC#Cc1ccc(Cl)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Method B A mixture of 400 g (0.96 mole) of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne, 1.3 L of ethanol and 300 ml of 40% aqueous methylamine was stirred at room temperature for 2 hr. Dropwise 2.8 l of water was added, and the resulting precipitate was collected by filtration to give a pale yellow solid, mp 70°-80° C. Recrystallization from ether gave pale yellow prisms, mp 80°-91° C.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:19]1[CH2:21][C@@H:20]1[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].Cl>C1COCC1>[OH:19][CH2:21][C@H:20]1[CH2:22][C@@H:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CC[C@H]1CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H]1C[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
1.6M n-Butyllithium/hexane solution (76 mL, 120.98 mmol) was added dropwise to a solution of diisopropylamine (12.24 g, 120.98 mmol) in THF (240 mL) at 0° C. over 12 min under argon atmosphere. The mixture was stirred at 0° C. for 30 min, and the reaction mixture was cooled to −78° C. A solution of methyl (S)-3-(oxiran-2-yl)propanoate (13.12 g, 100.81 mmol) in THF (10 mL) was added dropwise thereto at −78° C. over 12 min. The reaction mixture was stirred at −15° C. for 2 hr, and poured into cooled 0.5N hydrochloric acid (600 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 49→70% ethyl acetate/hexane) to give methyl (1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylate (2.27 g, 17.44 mmol, 17%) as a colorless oil.
Reaction SMILES: [CH2:1]1[O:29][C:28]2[CH:27]=[CH:26][C:5]([C:6]([CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][NH:17][C:16]4=[O:25])[CH2:11][CH2:10]3)=[O:7])=[CH:4][C:3]=2[O:2]1.[BH4-].[Na+]>CO>[CH2:1]1[O:29][C:28]2[CH:27]=[CH:26][C:5]([CH:6]([OH:7])[CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][NH:17][C:16]4=[O:25])[CH2:11][CH2:10]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(CN1CCC(N2C(=O)NCc3ccccc32)CC1)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCc2ccccc2N1C1CCN(CC(O)c2ccc3c(c2)OCO3)CC1
Yield: 64.1 %

Procedure:
In this example, 2.70 g of 1-(3,4-methylenedioxybenzoylmethyl)-4-[3,4-dihydro-2(1H)-quinazolinon-1-yl]-piperidine and 150 ml of methanol are mixed and stirred under ice-cooling. Then, 2.0 g of sodium borohydride is added to the stirred mixture over a period of one hour. Subsequently, the mixture is brought back to room temperature and stirred for 3 hours at room temperature and the reaction solution is concentrated. The resultant residue is mixed with 50 ml of water and the mixture is extracted with ethyl acetate (100 ml×2 and 50 ml×1). The extract is washed with water, dried and concentrated. The resultant viscous residue is mixed with 5 ml of methanol. The crystals deposited are separated by filtration, washed with methanol and dried to obtain 2.05 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 1.74 g of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.CCN(CC)CC.[Cl:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Cl)[N:24]=1>CCCCO>[Cl:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:14][CH:13]=2)[N:24]=1
Reactant: NCc1ccc(-c2ccccn2)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1nc(NCc2ccc(-c3ccccn3)cc2)c2[nH]cnc2n1
Temperature: 110 °C

Procedure:
4-(2-Pyridyl)benzylamine (2.0 g, 1.05 mmol) and 3 ml of NEt3 are added to a solution of 2,6-dichloropurine (2.3 g, 10 mmol) in 20 ml of n-BuOH. After heating at 110° C. for 3 h, the mixture is cooled to 20° C. and the solid is filtered off, washed with 5 ml of cold butanol and then dried under vacuum. Yd=85. M.p. >250° C. 1H NMR (d6-DMSO) δ 4.80 (s, 2H, CH2); 7.20 (m, 1H, Hpyridyl); 7.45 (d, 2H, Hphenyl); 7.72 (m, 2H, Hpyridyl); 7.95 (m, 3H, Hphenyl and H-8), 8.54 (d, 1H, J=4.8 Hz, Hpyridyl).
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.ClC1C=C[C:33]2[C:32]([C:36]([OH:38])=O)=[C:31](Cl)C=C[C:28]=2[N:27]=1.CCN(C(C)C)C(C)C.OCC1CCNC1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:27]4[CH2:28][CH2:33][CH:32]([CH2:36][OH:38])[CH2:31]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: O=C(O)c1c(Cl)ccc2nc(Cl)ccc12
Agent: OCC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(CO)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid 2,6-Dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and 3-(1-hydroxy-methyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6): δ 8.49 (t, J=6.16 Hz, 1H), 7.80 (d, J=9.28 Hz, 1H), 7.53-7.47 (m, 2H), 6.94 (d, J=9.32 Hz, 1H), 4.73-4.72 (m, 1H), 4.15 (s, 1H), 3.64-3.49 (m, 2H), 3.47-3.41 (m, 3H), 2.42 (s, 1H), 2.05-2.03 (m, 1H), 1.79-1.60 (m, 2H), 1.60-1.47 (m, 5H), 1.29-1.28 (m, 1H), 1.18-1.17 (m, 1H), 0.84-0.82 (m, 3H), 0.75-0.75 (m, 1H) m/z: 432.2 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#N)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[PH2]([O-])=[O:20].[Na+].C(O)(=O)C.[NH4+].[OH-]>[Ni].O.N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CN1CC=C(c2c[nH]c3ccc(C=O)cc23)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Raney nickel (ca 10 g) was added to a solution of the product from step (a) (5.0 g) and sodium hypophosphite (6.0 g) in a mixture of water (25 ml), glac. acetic acid (25 ml) and pyridine (50 ml) at 45° C. The resulting mixture was stirred at 45° C. for 1 hour, cooled and basified to pH 9 with 0.88 NH4OH. The mixture was filtered through Hyflo and the filtrate extracted with chloroform. The combined extracts were dried and evaporated in vacuo to give the desired product as an off-white solid which was recrystallised from ethanol (2.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[O:3]1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=O.CC(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:31][C:2]1([CH3:1])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([N:25]3[CH2:26][CH2:27][N:28]([CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)[CH2:29][CH2:30]3)[C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[O:3]1
Reactant: O=Cc1ccccn1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3c2OC(C)(C)C3)N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3c2OC(C)(C)C3)N2CCN(Cc3ccccn3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 1883 %

Procedure:
The title compound 9 was prepared by dissolving compound 5 (0.45 g, 0.98 mmol) in MeOH (10 mL) with 2-pyridine carboxaldehyde (110 μL, 1.18 mmol) and HOAc (3 μL, 50 μmol). Sodium cyanoborohydride (70 mg, 1.18 mmol) was added at 0° C. and reaction stirred 48 h at 25° C. Reaction was worked up by concentration in vacuo, extraction (CH2Cl2/K2CO3(aq)) and chromatography by reverse phase HPLC to give the title compound 9,461 mg(63%).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CC(C)([O-])C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: c1ccc(Cc2nnc(N3CCNCC3)c3ccccc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cc1
Temperature: 110 °C
Yield: 36.6 %

Procedure:
To a solution of 1-benzyl-4-piperazin-1yl-phthalazine (100 mg, 0.329 mmol) in 1 mL THF is added 4-bromo-benzotrifluoride (99 mg, 0.443 mmol), potassium tert-butoxide (55.3 mg, 0.493 mmol), XPhos [2-(Dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1′-1′-biphenyl] (15.7 mg, 0.033 mmol), and palladium (II) acetate (11 mg, 0.16 mmol) in a 2 dram screw-top vial. The vial is evacuated and flushed with argon. The reaction mixture was heated to 110° C. for 18 hrs. The mixture is then poured into water (50 mL), and the precipitate is isolated by filtration. The resulting solid is purified by flash chromatography on silica gel (10-70% EtOAc:heptanes) to provide the desired product as yellow crystals (54 mg, 37% yield).
Reaction SMILES: C([N:8]([CH2:39][CH3:40])[CH2:9][C:10]([NH:12][C@H:13]([C:25]([NH:27][C@H:28]([C:36]([NH2:38])=[O:37])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26])[CH2:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11])(OC(C)(C)C)=O.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>ClCCl>[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].[NH:8]([CH2:39][CH3:40])[CH2:9][C:10]([NH:12][C@H:13]([C:25]([NH:27][C@H:28]([C:36]([NH2:38])=[O:37])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:26])[CH2:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:11]
Reactant: CCN(CC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)C(N)=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)C(N)=O
Temperature: 5 °C

Procedure:
BOC-N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2 is dissolved in dichloromethane (~1:12 wt/wt), and to that solution is added TFA at ambient temperature. This is then stirred until HPLC indicates complete reaction (3-5 hours). The solution is concentrated to about 1/2 volume at 40-45° C. To this warm solution is added MTBE (~1:10 wt/wt vs. BOC-N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2) while maintaining the temperature >40° C. The mixture is slowly cooled to about 5° C. and stirred for 1 hour to ensure complete crystallization. The resulting solids are filtered, and washed with chilled MTBE. The solids are dried under reduced pressure and analyzed for content of TFA.N(Et)Gly-(L)-Asp(OBzl)-(L)-Cha-NH2 (HPLC wt/wt assay). Yield is generally nearly quantitative, purity >95A %.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]#[N:13])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[Li+].[Cl-]>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:12]([C:4]1[CH:3]=[C:2]([CH2:16][CH:15]=[CH2:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])#[N:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C(=O)OC)c(C#N)c1

Procedure:
A mixture of methyl 4-bromo-2-cyanobenzoate (230 mg, 0.96 mmol), allyl-tributyl-stannane (381 mg, 1.2 mmol), LiCl (126 mg, 2.87 mmol) and Pd(PPh3)4 (23 mg) in anhydrous toluene was refluxed under N2 overnight. Distilled off the solvent under reduce pressure, the residue was purified with prep-TLC to give the product methyl 2-cyano-4-(prop-2-en-1-yl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:14]#[N:15])[CH2:9][CH2:10]2)=[O:25])[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL flask was added 455 mg of 4-(4-chloro-phenyl)-piperidine-4-carbonitrile (2.06 mmol, 1.0 equiv), 500 mg of (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (2.06 mmol, 1.00 equiv), 1.10 g of BOP (2.47 mmol, 1.2 equiv), 1.15 mL TEA (8.24 mmol, 4.00 equiv) and 6 mL NMP. A stir bar was placed in the flask and the reaction solution was stirred overnight at room temperature under N2 atmosphere. The crude product was purified by normal phase HPLC (EtOAc-hexane as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carbonitrile: MS (ES) M+H expected=445.3, found=445.1.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[Cu](C#N)[C:31]#[N:32].N>CS(C)=O>[C:31]([C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=1[CH3:29])#[N:32]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CS(C)=O
Product: Cc1c(C#N)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 81.6 %

Procedure:
A solution of N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (0.5 g, 1.09 mmol) obtained in Example 35 and copper cyanide (300 mg 3.27 mmol) in dimethylsulfoxide (30 mL) was heated at 180° C. for 14 hours. To the reaction solution was added aqueous ammonia and the product was extracted with ethyl acetate. The extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 3:1) to obtain 360 mg (yield: 82%) of the title compound. Melting point: 135-136° C. (hexane-ethyl acetate).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1>>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ncccc1O
Product: CN1C(C(=O)Nc2ncccc2O)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 40 %

Procedure:
4-Hydroxy-N-(3-hydroxy-2-pyridyl)-2-methyl-2H-naphtho[2,1-e]1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-3-hydroxy-pyridine. Yield: 40% of theory; m.p. 255° C (decomp.).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11][N:12]([CH3:23])[CH2:13][C:14]([CH3:22])([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6]#[C:5]/[CH:4]=[CH:3]/[CH2:2][N:18]1[CH2:19][CH2:20][CH:15]([C:14]([CH3:22])([CH3:21])[CH2:13][N:12]([CH3:11])[CH3:23])[CH2:16][CH2:17]1
Reactant: CN(C)CC(C)(C)C1CCNCC1
Reactant: CC(C)(C)C#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(C)(C)C1CCN(C/C=C/C#CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
12 g (6.10-2 mole)of 1-bromo-6,6-dimethyl-2-hepten-4-yne (E/Z=3/1) in solution in 20 ml of N,N-dimethylformamide was added drop-wise to a mixture of 10 g (5.4×10-2 mole) of N,N,β,β-tetramethyl-4-piperidineethanamine and 14.9 g of potassium carbonate in 150 ml of N,N-dimethylformamide. The mixture was stirred for 48 hours at room temperature then poured into water. This was extracted several times with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. The residual oil obtained was purified by silica column chromatography, eluting with a 9/1 (v/v) methylene chloride/methanol mixture. After evaporation of the solvents under reduced pressure, 10.3 g (yield: 56%) of (E)-1-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N,N,β,β-tetramethyl-4-piperidineethanamine was obtained. The corresponding (Z)-2-butene-dioate was obtained from this in ethanol. M Pt=185°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2F)[C:19]#[N:20])=[CH:9][CH:8]=1.[H-].[Na+]>CN1C(=O)CCC1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:25][C:23]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[O:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OC[C@@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: COCCOCCOC
Product: N#Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Yield: 54.4 %

Procedure:
3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (28.9 g) was dissolved in 30 mL dry NMP and 270 mL dry diglyme under nitrogen and heated to 142° C. internal temperature. A suspension of sodium hydride (2.676 g of 60% NaH in mineral oil) in 6 mL of dry NMP and 54 mL of dry diglyme was added all at once via cannula while stirring. After 15 min the reaction was removed from heating and cooled 5 min, then poured into ice/1 L EtOAc/0.5 L 1 N HCl. The layers were separated and the organic layer washed twice with water, once with brine and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc) to provide 31 g of partially purified solid which was then crystallized from refluxing 3:1 MeOH/DCM, to give 15 g of desired product. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.33 (m, 2H), 7.28-7.24 (m, 1H), 7.23 (d, 1H) 7.19 (m, 1H), 7.0 (m, 3H), 5.12 (m, 1H), 5.04 (s, 2H), 4.37 (m, 1H), 4.03 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4](C2C=CC(F)=CC=2C)[CH:3]=1.[Cl:34][C:35]1[C:36](I)=[CH:37][C:38]([F:41])=[N:39][CH:40]=1>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=2)=[C:4]([C:36]2[C:35]([Cl:34])=[CH:40][N:39]=[C:38]([F:41])[CH:37]=2)[CH:3]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1cc(F)ncc1Cl

Procedure:
The title compound was prepared in analogy to example 73, from N-(6-chloro-4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 72, intermediate) and 5-chloro-2-fluoro-4-iodopyridine (CAS RN 659731-48-3) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic separation. Colorless oil (89%). MS (ESI): m/z=511.009 [M+H]+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:22]=[CH:21][C:10]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>C1COCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH2:12][O:11][C:10]1[CH:21]=[CH:22][C:7]([B:27]([OH:32])[OH:28])=[CH:8][C:9]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cc(Br)ccc1OCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCOC2CCCCO2)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
BuLi (2.5M, 6 ml) was added dropwise to a solution of 2-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethoxy)tetrahydro-2H-pyran (5 g) in THF (50 ml) at −78° C. under N2 during 3 minutes. After stirring at −78° C. for another 10 minutes, triisopropyl borate (3.8 ml) was then added dropwise during 2 minutes at −78° C. The mixture was stirred at −78° C. for further 30 minutes, then slowly warmed up to room temperature and stirred at room temperature for 30 minutes. The mixture was then quenched with acetic acid (10% in water, 20 ml), extracted with EtOAc (300 ml), washed with water (200 ml×3), dried over sodium sulphate, solvent removed under reduced pressure, the residue was taken in to toluene and then solvent removed under reduced pressure to take out traces of acetic acid (repeat 3 times) (4.5 g).