Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[CH:32]1([CH2:31][CH2:30][CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: ClCCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCC2CCCCC2)C3)nc1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and (3-chloropropyl)cyclohexane (0.179 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 408.3 (M+H)+, HRMS calcd for C25H34N3O2 408.2651 (M+H)+, found 408.2652, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=13.3 min, 100% purity.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH:18]=[N:17]1)=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[F:29][C:30]1[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1>C(#N)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:21]([C@H:20]2[N:16]([C:14](=[O:15])[C@@H:13]([CH2:12][N:3]([CH:1]=[O:2])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:17]=[CH:18][CH2:19]2)=[O:22])=[N:34][CH:35]=1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1N=CC[C@H]1C(=O)O
Reactant: Nc1ccc(F)cn1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of (5S)-1-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (100 mg, 0.26 mmol) and 5-fluoro-2-pyridinamine (37 mg, 0.33 mmol) in acetonitrile (10 mL) was added 4-methylmorpholine (39 mg, 0.39 mmol) and 2-chloro-4,6-bis(methyloxy)-1,3,5-triazine (49.5 mg, 0.28 mmol). The mixture was stirred at rt overnight. LCMS showed that the reaction was complete. The solvent was removed under vacuum and ethyl acetate was added. The mixture was washed with 10% KHSO4, sat. NaHCO3, brine, dried and concentrated. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (3:1 to 1:1) to provide the titled compound (108 mg, 85%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2ccc(Cc3ncc[nH]3)cc2)cc1

Procedure:
This substance is prepared analogously to Example 1 from 4-(1-imidazolylmethyl)-phenol and 4-methoxybenzyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27](C)[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.BrC1C=CC(C(F)(F)[F:68])=CC=1F>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:26]=2[F:68])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1cc(C(F)(F)F)ccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 16 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-((3-methyl-4-(trifluoromethyl)phenyl)-ethynyl)pyridazine (Intermediate 74) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene in 16% yield.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].OC(C(F)(F)F)=O.N1CC(C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4[CH2:51][CH2:52][O:53][C:44]=3[CH:43]=2)C1.ClCC(N1CCOCC1)=O>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][C:28]([N:30]6[CH2:43][CH2:44][O:53][CH2:52][CH2:51]6)=[O:29])[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=C(CCl)N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)N4CCOCC4)C3)ccc1-2

Procedure:
Following the procedure of 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and 4-(2-chloroacetyl)morpholine gave 471 isolated as a yellow solid (79 mg, 22%). LCMS: RT=3.17 min, [M+H]+=495. 1H NMR δ (ppm) (DMSO-d6): 8.25 (1 H, d, J=8.17 Hz), 8.05 (1 H, s), 7.17 (1 H, dd, J=8.24, 1.82 Hz), 7.03 (1H, d, J=1.77 Hz), 5.82-5.73 (1 H, m), 4.35-4.29 (2 H, m), 3.67-3.56 (2 H, m), 3.58-3.45 (5 H, m), 3.44-3.34 (6 H, m), 3.31 (2 H, s), 3.16 (2 H, t, J=6.11 Hz), 1.50 (6 H, d, J=6.59 Hz)
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[C:6]([C:21]#[N:22])=[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.CS(C1N=C(N2CCC(C3C=CC=CC=3)CC2)C(C#N)=C(OCC(F)(F)F)N=1)(=O)=O.[CH2:70]([CH2:72][NH2:73])[OH:71]>O1CCOCC1>[OH:71][CH2:70][CH2:72][NH:73][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)[C:6]([C:21]#[N:22])=[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:4]=1
Reactant: NCCO
Reactant: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Agent: CS(=O)(=O)c1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: N#Cc1c(OCC(F)(F)F)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 57c, 2-methylsulfanyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile was oxidized by 3-chloro-perbenzoic acid to 2-methanesulfonyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile which was then treated in crude form with ethanolamine in dioxane at 40° C. during 18 hours to yield the 2-(2-hydroxy-ethylamino)-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=422.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:4][CH:5]1[N:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCSC1NC(=O)C1CC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Reaction time: 18 h

Procedure:
To a vigorously stirred solution of 2.34 g of 4-allylthio-3-ethylazetidin-2-one in 20 ml of dimethylformamide were added 1.37 ml of methyl bromoacetate and 4.16 g of finely ground potassium carbonate. After 18 hours, the mixture was poured into 75 ml of water, was extracted into ethyl acetate (5×20 ml) and the combined organic extracts were washed with water (6×15 ml), dried over MgSO4 and evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compound as a yellow oil (3 g).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH2:8](OCC)C.[CH2:13]([C@H:15]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:14]>>[CH2:13]([C@H:15]1[C@:19]([OH:20])([CH3:8])[CH2:18][CH2:17][N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:14]
Reactant: CC[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Product: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (11.69 g), 3 mol/L methylmagnesium bromide-diethyl ether solution (13.55 mL) and benzyl (2S)-2-ethyl-3-oxopyrrolidine-1-carboxylate (3.35 g), the title compound was obtained as colorless oil (yield: 2.84 g, yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.F[C:20]1C=C(C)C=C(F)C=1B1OC(C)(C)C(C)(C)O1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:20])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: Cc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: Cc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 125) gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:5](/[CH:18]=[CH:19]/[C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][S:3]1.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[OH:28][CH:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)/[CH:19]=[CH:18]/[C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 3-7 (0.4 g, 1.0 mmol) in 12 mL 5:1 MeOH:acetic acid was added sodium cyanoborohydride (100 mg, 1.4 mmol) and the resulting solution was stirred overnight at room temperature. The solution was quenched with water and was concentrated in vacuo. The concentrate was extracted with ethyl acetate and washed with 2M Na2CO3 and then brine, after which it was dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 60% ethyl acetate/hexanes to yield 400 mg of 3-8 as a colorless oil. Data shown is for the major diastereomer. 1H NMR (400 MHz, CDCl3): δ 7.35–7.21 (m, 5H), 5.84 (dd, 1H), 5.66 (dd, 1H), 4.46 (q, 1H), 4.23 (q, 1H), 4.14 (q, 2H), 3.68–3.37 (m, 2H), 2.97 (dd, 1H), 2.88 (m, 2H), 2.78 (m, 1H), 2.30 (t, 2H), 1.64–1.30 (m, 8H), 1.27 (t, 3H); MS (+ESI): m/z 406.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:16]([N+:21]([O-:23])=[O:22])=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:15][C:14]2[C:16]([N+:21]([O-:23])=[O:22])=[CH:17][C:18]([O:19][CH3:20])=[C:12]([Br:11])[CH:13]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: COc1cc([N+](=O)[O-])c(N)cc1Br
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: COc1cc([N+](=O)[O-])c(NC(=O)c2ccc(Cl)nc2)cc1Br

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 3-bromo-4-methoxy-6-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (DMSO-d6): 10.84 (s, 1H), 8.93 (d, J=2.4, 1H), 8.34-8.30 (m, 1H), 7.98 (s, 1H), 7.76 (d, J=8.4, 1H), 7.70 (s, 1H), 3.97 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:33]=[CH:32][N:31]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COc1cccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cccc(Sc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Yield: 57.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((3-methoxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (103 mg, 0.24 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (55 mg, 0.36 mmol),), N,N-diisopropylethylamine (126 μl, 0.72 mmol) and tert-butanol as a solvent according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification to give 70 mg (57% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N+]=[N-])[CH:6]=[CH:7][CH:8]=1.[CH:24]([CH:26]=[CH2:27])=[O:25]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:27][CH:26]2[CH:24]=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: C=CC=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=CC1CC1(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
a solution of bis[3-(trifluoromethyl)phenyl]diazomethane, prepared as in Example 84 from 3,3'-(trifluoromethyl)benzophenone hydrazone (29.9 g) and activated manganese dioxide (30 g) in dichloromethane (150 mL) was added to a solution of acrolein (9.9 mL) in heptane (90 mL) over 15 minutes at 40° C. The solution was heated at 55° C. for 5.5 hours, then the dichloromethane was distilled off and replaced with heptane (100 mL). After the mixture was heated at 90° C. overnight, the solvent was removed in vacuo and the residue was purified by HPLC (dichloromethanehexane; 1:1). Evaporation of the appropriate fractions yielded 30.5 g of 2,2-bis[3-(trifluoromethyl)phenyl]cyclopropanecarboxaldehyde. Crystallization of a portion from hexane gave the analytical sample, 106°-108° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH:14]=1)(C(C)(C)C)(C)C.[F:32][C:33]([F:54])([F:53])[C:34]1[CH:35]=[C:36]([C@@H:44](OC(=N)C(Cl)(Cl)Cl)[CH3:45])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.[H+].[B-](F)(F)(F)F>CCOCC>[F:32][C:33]([F:53])([F:54])[C:34]1[CH:35]=[C:36]([C@H:44]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:10]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C1CC=C(O[Si](C)(C)C(C)(C)C)C(c2ccc(F)cc2)C1C(=O)OCC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 9.09 g (26.9 mmol) of the first eluting isomer diethyl (1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step D) and 21.5 g (53.5 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (step E) in 250 mL of cyclohexane/1,2-chloroethane (3/1) under nitrogen atmosphere at −5° C. was added 0.51 mL (3.58 mmol) of 54% HBF4 in ether. The reaction mixture was stirred at −5° C. to at 0° C. for 2 hr then diluted with ether. The mixture was washed with sat. aq. NaHCO3. The organic layer was dried over drying agent, filtered and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes (1/4) to give 9.2 g of the title compound as an oil. 1H-NMR (CDCl3): δ: δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, t, J=8.5 Hz), 4.43 (1H, q, J=6.0 Hz), 4.20-4.10 (2H, m), 3.80-3.73 (2H, m), 3.36 (1H, m), 2.90-2.76 (2H, m), 2.40 (1H, m), 2.28 (1H, m), 1.63-1.55 (2H, m), 1.33 (3H, d, J=6.0 Hz), 1.25 (3H, t, J=7.2 Hz), 0.82 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10](=O)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CCO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(=O)CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CCO
Solvent: O
Product: CC(CN(CC(=O)O)C(=O)OC(C)(C)C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of [tert-Butoxycarbonyl-(2-oxo-propyl)-amino]-acetic acid (1 eq), aniline (1.2 eq) and Ti(OiPr)4(1.25 eq) was stirred at RT for 30 min under N2 flow. The mixture was diluted with dry EtOH (0.8 M) and NaBH3(CN) (0.67 eq) was added. The reaction mixture was stirred for 24 h, after which water was added and the resulting white, inorganic precipitate was filtered, and washed with EtOH. The filtrate was concentrated under reduced pressure and the resulting crude was diluted with EtOAc. The solution was extracted with 1N NaOH and the aqueous phase was washed with EtOAc twice. The aqueous phase was acidified to pH 1 by addition of conc. HCl at 0° C. and washed with EtOAc. The pH of the collected aqueous phase was adjusted to pH 3-4 and product extracted with EtOAc (5×). The collected organic phases were dried (Na2SO4), filtered and evaporated to provide LL1 as a transparent oil. MS (ES) C16H24N2O4 requires: 308 found: 309 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: CN1CCCC1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCCC1CCOS(C)(=O)=O

Procedure:
The 1-methyl-2-pyrrolidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:32][CH3:33])[CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([OH:24])=[O:23])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:32][CH3:33])[CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCCC1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCCC1C(=O)O

Procedure:
A solution of 6.7 g. of benzyl 9-benzoyl-6-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylate in 250 ml. of ethyl acetate was hydrogenated over 1 g. of palladium-on-charcoal until the required amount of hydrogen had reacted. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was slurried in ether and the resulting solid was collected by filtration to give 1.8 g. of the title compound; m.p. 157-159°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:6]#[N:7].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:31])C(=O)C1.CCCCCCC>ClCCCl>[Br:31][CH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C#N)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: ClCCCl
Product: COc1cc(C#N)ccc1CBr
Temperature: 82 °C
Reaction time: 0.5 h

Procedure:
14.7 g (0.1 mol) of 3-methoxy-4-methylbenzonitrile were dissolved in 210 ml of 1,2-dichloroethane, bromination was carried out at 82° C. in the presence of catalytic amounts of AIBN with 19.1 g (0.11 mol) of NBS in portions over the course of 1 h and, after the addition was complete, the mixture was stirred at 82° C. for a further 30 min. Addition of n-heptane was followed by removal of precipitated succinimide, and the solvent was stripped off. The product contained, besides small amounts of precursor, also traces of the corresponding benzal bromide. 1H-NMR (DMSO-d6; δ in ppm): 7.60 (dd, 1H); 7.50 (d, 1H); 7.40 (dd, 1H); 4.68 (s, 2H); 3.96 (s, 3H)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1>CC#N>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:1])=[CH:15][NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A solution of N-chlorosuccinimide (4.13 g, 31 mmol) in MeCN (50 mL) was added dropwise to a stirred solution of 7-bromo-1-(2H)-isoquinolone (6.6 g, 29.5 mmol) in MeCN (150 mL) which was heating under reflux. The mixture was heated under reflux for an additional 3 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 7-bromo-4-chloro-1(2H)-isoquinolone (6.72 g, 26.0 mmol) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Temperature: 101.5 °C
Yield: 94.9 %

Procedure:
Potassium carbonate (3.3 g, 24 mmol) and 1-methylpiperazine (2.8 g, 29 mmol) were dissolved in 16 mL of water and then 4-fluorobenzaldehyde (2.0 g, 16 mmol) was added. The mixture was heated at reflux (100-103° C.) under a nitrogen atmosphere for 21 hours when HPLC showed that the reaction was complete. The solution was cooled to 20-25° C. and then extracted with methylene chloride (2×30 mL). The methylene chloride extracts were combined, washed with water (2×30 mL), and then concentrated at reduced pressure to a yellow oil (3.1 g, 96% yield). The crude solid was triturated with hexanes to afford crystals. mp 60.5-62.0° C. 1H NMR (CDCl3) δ 9.77 (s, 1H), 7.74 (d, J=10 Hz, 2H), 6.91 (d, J=10 Hz, 2H), 3.40 (m, 4H), 2.53 (m, 4H), and 2.34 (s, 3H).