Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[Cl:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(-c3cc4cc(OCc5ccccc5)ccc4[nH]3)cc2)cc1
Reactant: ClCCl
Product: Clc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A flask was charged with 5-benzyloxy-2-(4-benzyloxy-phenyl)-1 H-indole No. 141 (8.0 g, 20.0 mmole) and CH2Cl2 (50 ml). The reaction was cooled to 0° C. and n-chlorosuccinimide (2.9 g, 22 mmole) was added. The reaction was stirred at 0° C. for 20 min. The reaction was then washed with 10% sodium sulfit solution, dried over MgSO4, and concentrated. To the resulting brown solid was added MeOH and the mixture was stirred for 15 min. The solid was filtered to give 6.8 g of a tan solid (78%). Mp=157-160° C.; 1H NMR (DMSO) 11.5 (s, 1 H), 7.80 (d, 2 H, J=7.0 Hz), 7.42−7.28 (m, 11 H), 7.17 (d, 2 H, J=8.7 Hz), 7.01 (d, 1 H, J=2.2 Hz), 6.88 (dd, 1 H, J=8.8 Hz, J=2.4 Hz), 5.17 (s, 2 H), 5.13 (s, 2 H); MS eI m/z 439 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O>C1(C)C=CC=CC=1>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Product: c1ccc(CNc2ccccn2)nc1
Reaction time: 16 h

Procedure:
To a flask were added 4.7 g of 2-aminopyridine, 5.35 g of 2-pyridinecarboxaldehyde, and 75 ml toluene. The flask was equipped with a Dean-Stark trap and heated to reflux under nitrogen. After 16 hours, the toluene was removed and 100 ml ethanol were added followed by 2.1 g of sodium borohydride. The mixture was stirred at 22 C under nitrogen for 1 hour, and then 50 ml of water were added slowly. Following removal of the ethanol, aqueous ammonium chloride was cautiously added resulting in gas evolution. The product was extracted twice with 50 ml ethyl acetate and washed with 30 ml water. After solvent removal, the product was purified by silica gel chromatography using 5% methanol in ethyl acetate resulting in an orange oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].[Br:37][C:38]1[CH:43]=[CH:42][C:41](O)=[C:40]([CH3:45])[CH:39]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([O:30][CH2:29][CH2:28][C:26]2[CH:25]=[N:24][C:23]3[N:17]([CH2:15][CH3:16])[C:18]4[N:36]=[CH:35][CH:34]=[CH:33][C:19]=4[N:20]([CH3:32])[C:21](=[O:31])[C:22]=3[CH:27]=2)=[C:40]([CH3:45])[CH:39]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(Br)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A solution of DIAD (0.44 mL, 2.40 mmol) in THF (1.0 mL) was added dropwise to an ice-cold solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (480 mg, 1.61 mmol), 4-bromo-2-methylphenol (318 mg, 1.70 mmol) and PPh3 (629 mg, 2.40 mmol) in THF (20 mL) at 25° C. The mixture was stirred at 0° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (Hexane:EtOAc, 7:3) to yield the title compound (437 mg, 58% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.Cl.CN(C)CCCN=C=NCC.[N+:30]([C:33]1[CH:34]=[C:35]([CH:57]=[C:58]([N+:60]([O-:62])=[O:61])[CH:59]=1)[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:56])/[CH:47]=[CH:48]/[C:49]1[CH:54]=[CH:53][C:52](O)=[CH:51][CH:50]=1)=[O:37])([O-:32])=[O:31]>ClCCl.CN(C)C1C=CN=CC=1>[N+:30]([C:33]1[CH:34]=[C:35]([CH:57]=[C:58]([N+:60]([O-:62])=[O:61])[CH:59]=1)[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46](=[O:56])/[CH:47]=[CH:48]/[C:49]1[CH:50]=[CH:51][C:52]([O:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:16])([F:17])[F:1])=[CH:8][CH:9]=2)=[CH:53][CH:54]=1)=[O:37])([O-:32])=[O:31]
Reactant: O=C(O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: O=C(/C=C/c1ccc(O)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
8.61 g (0.0347 Mol) of 4-(4,4,4-trifluorobutoxy)benzoic acid are suspended in 100 ml of dichloromethane. 0.42 g (0.0035 Mol) of 4-Dimethylaminopyridine are added at room temperature. 7.98 g (0.04163 Mol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. 15.90 g (0.0347 Mol) of 6-[((2E)-{4-hydroxyphenyl}prop-2-enoyl)oxy]hexyl 3,5-dinitrobenzoate dissolved in 50 ml of dichloromethane are added dropwise to the solution at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The mixture is acidified with HCl 25%. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 600 g silica gel using toluene:ethyl acetate (99:1) as eluant and crystallization from ethyl acetate/hexane (1:2) yielded 18.82 g (79%) of 6-{[((2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl)oxy]}hexyl 3,5-dinitrobenzoate as white crystals.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Br:13][C:14]1[CH:22]=[C:18]([C:19]([OH:21])=O)[C:17]([OH:23])=[CH:16][CH:15]=1.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29][NH2:30].Cl>CN(C)C1C=CN=CC=1.O1CCCC1>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH2:29][NH:30][C:19](=[O:21])[C:18]2[CH:22]=[C:14]([Br:13])[CH:15]=[CH:16][C:17]=2[OH:23])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC.HCl hereafter.; 192 mg, 1 mmol) was added to a mixture of 5-bromosalicylic acid (217 mg, 1 mmol), 3,5-bis(trifluoromethyl)benzylamine (243 mg, 1 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (244.8 mg, 55.4%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[N:10]1([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:10]1([C:16]2[CH:17]=[C:18](/[CH:19]=[N:1]/[C:2]3[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(N2CCOCC2)c1
Reactant: N#Cc1ccc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(/N=C/c2cccc(N3CCOCC3)c2)cn1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
The mixture solution of 5-amino-pyridine-2-carbonitrile (9.3 g, 78.4 mmol), 3-morpholin-4-yl-benzaldehyde (15.0 g, 78.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-{[1-(3-morpholin-4-yl-phenyl)-meth-(E)-ylidene]-amino}-pyridine-2-carbonitrile (22.9 g, quant.) as a light yellow solid: MS (ESI) M+1=293.0.
Reaction SMILES: Cl[B:2]([Cl:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>ClCCCl>[CH3:10][N:11]([B:2]([Cl:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: ClB(Cl)c1ccccc1
Reactant: CNc1cccc(OC)c1
Solvent: ClCCCl
Product: COc1cccc(N(C)B(Cl)c2ccccc2)c1

Procedure:
N-methyl-3-methoxyanilinochlorophenylborane was prepared by adding dichlorophenylborane (100 mmol) to a solution of N-methy-3-methoxyaniline (100 mmol) in 1,2-dichloroethane (100 mL) at 0° C. The resulting mixture was refluxed for 2 h under a rapid stream of nitrogen to remove the HCl formed. The mixture was cooled to give a 0.8 M cloudy solution of the title compound which could be stored at 0°C. for more than 6 weeks without deterioration.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[C:32]([O:38][CH3:39])[CH:31]=1>O1CCCC1>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([OH:35])[CH:15]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]23)=[C:32]([O:38][CH3:39])[CH:31]=1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Reactant: COc1cc(F)ccc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(F)ccc1C(O)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
To a solution of 0.500 g (2.06 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one (step 4.1) in dry tetrahydrofuran (20 mL) under argon at −40° C. was added 2.48 mL (2.48 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −40° C. for 10 min and 0.636 g of 4-fluoro-2-methoxy-benzaldehyde (4.13 mmol) diluted in 5 ml of dry tetrahydrofuran was added. The reaction was allowed to increase to room temperature for 2 h. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 2% of methanol and 0.2% of ammonia) to afford 0.505 g of a white solid (62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19]C)=O)[CH2:13][CH2:12]1.[NH2:21][NH2:22].O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:21][NH2:22])=[O:19])[CH2:13][CH2:12]1
Reactant: NN
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Solvent: O
Solvent: CCO
Product: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Yield: 90.9 %

Procedure:
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccc5ccccc5n4)cc3)cc2)CC1
Temperature: 60 °C

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.181 g, 0.5 mmol) was dissolved in DMF and then sodium hydride (60% in mineral oil, 0.028 g, 0.7 mmol) was added. After 20 minutes 2-chloroquinoline (0.1145 g, 0.7 mmol) was added and the reaction was heated to 60° C. for 3 hours. No product was observed by analytical LCMS so the reaction was heated to 100° C. overnight. After cooling the reaction was submitted to standard aqueous workup to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:23]1[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(N2CCC(F)(F)CC2)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(N2CCC(F)(F)CC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 12 step B from a mixture of 6-chloro-2-(4,4-difluoro-piperidin-1-yl)-4-phenyl-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. Pale yellow solid (55 mg, 74%). LC-MS: 403 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([NH:19][C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:39](OCC)(=O)C>CN(C)C=O>[Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([N:19]([CH3:39])[C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ncc(-c2ccc(C(F)(F)F)cc2)o1)c1cccc2c1CC(O[Si](C)(C)C(C)(C)C)CC2
Reaction time: 0.08 h
Yield: 18 %

Procedure:
The product of Example 18D (300 mg, 0.615 mmol) in 5 mL N,N-dimethylformamide was treated with NaH (60% dispersion, 32 mg, 0.8 mmol) at rt. After stirring for 5 minutes, iodomethane (0.15 mL, 2.4 mmol) was added. The reaction was stirred at rt for 24 h, then it was poured into ethyl acetate and washed several times with water and once with brine. The organic layer was dried over Na2SO4 and was concentrated. The concentrate was purified on silica gel, eluting with 5% ethyl acetate-hexane and afforded the title compound as a brown oil (56 mg, 18%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of methyl indole-6-carboxylate (1.0 g) in N,N-dimethylformamide (10 mL), potassium carbonate (1.2 g) and benzyl chloride (1.4 g) were added at room temperature, and then the reaction mixture was stirred at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was quenched with water, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (681 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:12]2[N:11]3[CH2:13][CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C@H:10]3[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([F:28])[CH:3]=1.[Cl-].[CH3:30][Zn+].O>C1COCC1.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].Cl[Pd]Cl>[F:22][C:19]([F:21])([F:20])[C:18]([NH:17][C@H:16]1[C@@H:10]2[N:11]([C:12]3[C:2]([CH3:30])=[CH:3][C:4]([F:28])=[CH:5][C:6]=3[O:7][C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=32)[CH2:13][CH2:14][CH2:15]1)=[O:23]
Reactant: C[Zn+]
Reactant: O=C(N[C@@H]1CCCN2c3c(Br)cc(F)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)cc2c1N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of trans-N-(6-bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (300 mg, 0.65 mmol) in THF (7 mL) was added ferrocene PdCl2 (10 mg, 14 mmol) and the reaction mixture was stirred for 10 min. Methylzinc chloride (0.81 mL) was added dropwise whereafter the reaction mixture was heated to 60° C. After 3 h ferrocene PdCl2 (20 mg, 28 μmol) and methylzinc chloride (0.3 mL) were added and the reaction mixture was heated at 80° C. for another hour. Water was added at room temperature, and the reaction mixture was extracted with ether and water. The ether solution was washed with brine, dried (Na2SO4) and the volatiles were removed under reduced pressure. After purification by HPLC the title compound was obtained (108 mg, 39%). Data: 1H-NMR (400 MHz, CDCl3) 1.56-1.72 (m, 2H), 1.79-1.93 (m, 2H), 2.37 (s, 3H), 2.79-2.86 (m, 1H), 3.44-3.52 (td, J=12.0, J=3.0, 1H), 4.27-4.29 (d, J=2.5, 1H), 4.85-4.91 (m, 1H), 6.70-7.32 (6 ArH), 7.63-7.70 (br, 1H). (m/z)=395 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:35])([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[CH:23]([F:25])[F:24]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][C:22]([F:21])([F:35])[CH:23]([F:24])[F:25])=[CH:34][CH:33]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OC(F)(F)C(F)F)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)C(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-(1,1,2,2-tetrafluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 441.83 g/mol.
Reaction SMILES: [N+:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2)#[C-:2].[Si:13]([O:20][NH2:21])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C(Cl)(Cl)Cl>[Si:13]([O:20][N:21]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([N+:1]#[C-:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: [C-]#[N+]c1ccc2c(c1)CCC2=O
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: [C-]#[N+]c1ccc2c(c1)CCC2=NO[Si](C)(C)C(C)(C)C
Yield: 74.9 %

Procedure:
5-isocyano-2,3-dihydroinden-1-one (6) (3.00 g, 19.1 mmol) was combined with 1.4 eq. of O-(tert-butyldimethylsilyl)hydroxylamine (3.94 g, 26.7 mmol) and TsOH-H2O (0.363 g, 1.91 mmol) in 100 mL CHCl3 and heated to reflux overnight. TLC showed a small amount of remaining starting material and two non-polar spots corresponding to the oxime isomers. The reaction mixture was filtered and concentrated to a brown semi-solid, then purified immediately by loading onto a silica column with DCM and eluting with 1% MeOH/DCM to give 4.1 g (75%) of 5-isocyano-2,3-dihydroinden-1-one O-tert-butyldimethylsilyl oxime (7).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[N:3]1[CH2:8][CH2:7][C:6](=[N:9][OH:10])[CH2:5][CH2:4]1.P([O-])(O)(O)=O.[K+].[C-:18]#[N:19].[K+]>O>[CH3:1][N:2]([CH3:11])[N:3]1[CH2:8][CH2:7][C:6]([NH:9][OH:10])([C:18]#[N:19])[CH2:5][CH2:4]1
Reactant: [C-]#N
Reactant: CN(C)N1CCC(=NO)CC1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: CN(C)N1CCC(C#N)(NO)CC1
Temperature: 5 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
12.4 g 1-Dimethylamino-piperidin-4-one oxime (from Step 1) is dissolved in 160 ml water. 49.3 g potassium dihydrogenphosphate is added. The resulting yellow suspension is cooled to 5° C., and a solution of 11.24 g potassium cyanide in 40 ml water is added. The mixture is stirred at room temperature for 2 days, then extracted with ethyl acetate, the organic layer dried over sodium sulfate, and the solvent evaporated, to give 7.8 g 1-Dimethylamino-4-hydroxyamino-piperidine-4-carbonitrile. 1H-NMR (CDCl3): 5.60 ppm (s, broad, 1H), 5.10 ppm (s, broad, 1H), 2.92 ppm (m, 2H), 2.61 ppm (m, 2H), 2.33 ppm (s, 6H), 2.10 ppm (m, 2H), 1.70 ppm (m, 2H).