Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH2:18][C@H:17]([NH:16][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=2)[CH2:26][CH2:25]3)[CH2:28][CH2:29]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C4CCCCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Cyclohexylbenzoic acid (0.50 g, 2.4 mmol) was dissolved in thionyl chloride (20 mL) and heated at reflux for 30 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (96 mg, 0.43 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (62 μL, 0.45 mmol) in methylene chloride (20 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 150 mg (85%) of the title compound as white crystals: mp 224-226° C.; [α]21D -43° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 431 (2, M+).
Reaction SMILES: [N+](C1C=C(C=CC=1)C([O:9][C@@H:10]1[CH2:14][C@@H:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]1[CH3:23])=O)([O-])=O.CO>C1COCC1.O>[CH2:16]([O:15][C@@H:13]1[CH2:14][C@@H:10]([OH:9])[C@@H:11]([CH3:23])[CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H]1C[C@H](OCc2ccccc2)C[C@H]1OC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (1R*,2S*,4S*)-4-(benzyloxy)-2-methylcyclopentyl 3-nitrobenzoate (example 25; 11.5 g; 32.5 mmol) in THF (80.0 mL) and MeOH (40.0 mL) LiOH (1.17 g; 48.7 mmol) dissolved in water (40.0 mL) is added. The reaction mixture is stirred at ambient temperature for one hour and concentrated under reduced pressure. The residue is diluted with water and extracted with dichloromethane. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/tert-BuOMe—80:20 to 50:50) to yield 5.9 g of the title compound as pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:30][CH2:31][CH3:32])[C:28]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC(=O)C1C=C(OCC)C([Cl:46])=C(OCC)C=1)C.ClC1C(OCC)=CC(CN2CCC(NC(=O)C3C=C(OC)C=C(CO)C=3)CC2)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[Cl:46][C:28]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([OH:24])[CH:17]=3)[CH2:10][CH2:9]2)=[CH:26][C:27]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Agent: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 257) was reacted with 4-chloro-3,5-diethoxy-benzaldehyde (example 219), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless amorphous solid. MS: 463.3 (MH+).
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@@H:30](C(O)=O)[CH2:31][C:32](=[O:34])[NH2:33].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>FC(F)(F)C(O)=O.CN(C=O)C>[NH:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@@H:30]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:31][C:32](=[O:34])[NH2:33]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reactant: CC(C)(C)OC(=O)N[C@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CNC(=O)[C@@H](CC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reaction time: 0.17 h

Procedure:
In 10 ml of trifluoroacetic acid is dissolved 0.80 g of BOC-Gly-MePhe-NHNHCSNH2 and the solution is shaken for 10 minutes, concentrated, treated with ether and filtered to obtain a powder. This powder is dissolved in 10 ml of DMF, and after ice-cooling, the solution is neutralized with 0.20 ml of TEA followed by addition of 0.47 g of BOC-(D)-Asn-OH, 0.40 g of HONB and 0.45 g of DCC. The mixture is stirred for 20 hours, the precipitated DCU filtered off, the solvent distilled off and the residue dissolved in n-butanol. The solution is washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is treated with ether and filtered to obtain a powder, which is further reprecipitated from methanol-ether. Yield 0.69 g; m.p. 124°-127° C.; [α]D24 -42.5° (c=1.0, DMF); Rf1 0.16.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.O>[CH:19]1([C:24]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CCCC1
Reactant: C[C@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](NC(=O)C1CCCC1)C(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Alanine (16.8 g, 189 mmol) and 57.8 ml (415 mmol) of triethylamine are dissolved in 200 ml of dichloromethane and 52.7 ml (415 mmol) of trimethylsilyl chloride are added dropwise. After addition is complete, the mixture is stirred for 1 h at room temperature and for 1 h at 40° C. After this, the batch is cooled to −10° C. and cyclopentanecarbonyl chloride (25.0 g, 189 mmol) is added dropwise and the mixture is stirred at this temperature for 2 h. The reaction mixture is treated with 100 ml of water with cooling, stirred for 10 min and and filtered with suction. The residue is washed with water and diethyl ether and dried at 60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.CN([C:16]([O:20][N:21]1N=NC2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CNOC>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:21]([O:20][CH3:16])[CH3:22])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)Cc1ccc(O)cc1Br
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(O)cc1Br
Yield: 97.2 %

Procedure:
A mixture of 2-(2-bromo-4-hydroxyphenyl)acetic acid (0.67 g), HATU (1.33 g), triethylamine (0.35 g) and N,O-dimethylhydroxylamine hydrochloride (0.34 g) in dichloromethane (30 mL) was stirred overnight, to which water (30 mL) was added. The organic layer was separated. The water layer was extracted by ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (773 mg).
Reaction SMILES: C(N(CC)CC)C.[P:8]([O-:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[C:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)(=[O:18])[CH3:17]>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(OCC)(=O)C>[C:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])=[CH:23][CH:22]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(COC(C)=O)cc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 9.7 mL (0.057 mole) of triethylamine and 2.4 grams (0.002 mole) of tetrakis(triphenylphosphine)palladium(0) was stirred, and 7.3 mL (0.057 mole) of diethyl phosphite was added. To this was added 13.2 grams (0.057 mole) of 4-bromophenylmethyl acetate. The reaction mixture was warmed to about 100° C., where it stirred for 30 minutes. The reaction mixture was cooled, and 200 mL of ethyl acetate was added. The resultant solid was collected by filtration, and washed with 50 mL of ethyl acetate. The combined wash and filtrate were concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 3:7 heptane:ethyl acetate as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.1 grams of 4-(diethylphosphono)phenylmethyl acetate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21]CC)=O)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.C[N:44](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([NH2:44])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(N(C)Cc3cccnc3)cc2c1=O
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(Cc1cccnc1)c1cc2c(=O)c(C(N)=O)cn(-c3ccc(F)cc3)c2cc1F
Reaction time: 8 h
Yield: 27 %

Procedure:
Compound U (26 mg, 0.062 mmol, 1.0 eq), ammonium chloride (6.6 mg, 0.12 mmol, 2.0 eq), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (28 mg, 0.074 mmol, 1.2 eq) and N,N-diisopropylethylamine (43 μL, 0.25 mmol, 4.0 eq) were dissolved in DMF (0.5 mL) and stirred overnight. The reaction was diluted with ethyl acetate and washed with water (2×). The aqueous phase was back extracted with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography afforded 7.0 mg (27%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=4.4 Hz, 1H), 8.48-8.45 (m, 3H), 7.76-7.72 (m, 3H), 7.67 (dt, J=7.8, 1.7 Hz, 1H), 7.58 (d, J=4.4 Hz, 1H), 7.51 (t, J=8.7 Hz, 2H), 7.35 (dd, J=7.7, 4.9 Hz, 1H), 6.81 (d, J=14.0 Hz, 1H), 4.41 (s, 2H), 2.83 (s, 3H); ES-MS [M+1]+: 421.2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[F:30][C:31]([F:36])([F:35])[C:32]([CH3:34])=[O:33]>O1CCCC1>[F:30][C:31]([F:36])([F:35])[C:32]([OH:33])([CH3:34])[C:29]#[C:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:16]2[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=2)(=[O:20])=[O:21])=[CH:23][CH:24]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.42 h
Yield: 49.4 %

Procedure:
To a solution of diisopropylamine (0.37 mL, 2.66 mmol) in tetrahydrofuran (11 mL) at -20° C. was added n-butyllithium (0.9 mL of 2.5M solution in hexanes, 2.25 mmol) and the resulting solution was stirred for 25 minutes at -20° C. before being cooled to -78° C. To this was added a solution of 4-(4-pyridylsulfonyl)phenylacetylene (0.5 g, 2.05 mmol) in tetrahydrofuran (3 mL) over a five minute period. The mixture was stirred for an additional 15 minutes at -78° C. To this was added 1,1,1-trifluoroacetone (0.20 mL, 2.25 mmol) in one portion. After stirring the mixture at -78° C. for 20 minutes, it was quenched with water, warmed to ambient temperature and the pH adjusted to 7.0 with saturated aqueous NH4Cl . The solution was evaporated and the resulting residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed (brine), dried and evaporated. The resulting brown oil was purified by chromatography, with ethyl acetate:dichloromethane as the eluent (1:5), to give the title compound as a white solid (0.36 g, 50%); mp 122°-125° C.; NMR (CDCl3): 1.73 (s,3, CH3), 3.37 (s,1, OH), 7.61 (d,2, J=8.2, At), 7.76 (d,2, J=5.1, Ar), 7.93 (d,2, J=4); MS: m/z=356(M+ 1). Analysis for C16H12F3NO3S: Calculated: C, 54.08; H, 3.40; N, 3.94; Found: C, 53.99; H, 3.41; N, 3.75.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccnc2)CO1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
6-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.5 mmol) was dissolved in 15 mL DMF and stirred for 5 min at RT. Sodium hydride (540 mg, 13.5 mmol) was added portionwise at RT under nitrogen. 3-(2-Methyl-oxiranyl)-pyridine (800 mg, 5.9 mmol) was diluted in 5 mL DMF and added dropwise at the same temperature and stirred for 16 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water (30 mL) and filtered. The residue was crystallized in EtOH (1 mL) and ether (40 mL) and purified by reverse phase chromatography to obtain 620 mg of 1-(6-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.77 (s, 1H), 8.5 (d, 1H), 8.45 (s, 1H), 7.71 b(s, 1H), 7.17 b(s, 1H), 7.06 (d, 1H), 6.97 (t, 1H), 5.12 b(s, 1H), 4.3 b (s, 1H), 3.78 (m, 1H), 3.62 (m, 1H), 3.14 (m, 1H), 2.63 (m, 2H), 2.57 (s, 3H), 2.5 b(s, 2H), 1.53 (s, 3H). Separation by chiral HPLC provided enantiomers 57a and 57b.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl.O>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:12][C:6]2([C:4]([O:3][CH3:2])=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: COC(=O)C1(N)CCCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NS(=O)(=O)c2ccc(OC)cc2)CCCCC1
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid methyl ester hydrochloride (32 g, 165 mmol) was suspended in DCM (1000 ml), and diisopropylethylamine (84.9 ml, 496 mmol) was added thereto. A solution of 4-methoxybenzenesulfonyl chloride (51.2 g, 248 mmol) dissolved in DCM (150 ml) was added dropwise at 0° C., and stirring was carried out overnight at room temperature. Aqueous 1 M HCl (150 ml) and water (50 ml) were added and the phases were separated. The organic phase was dried over sodium sulfate and concentrated to dryness. The product was purified by column chromatography on silica gel (DCM/methanol 99:1).
Reaction SMILES: [BH4-].[Na+].[C:3]12([CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16](=[O:24])[CH2:17][O:18][CH2:19][C:20](OC)=[O:21])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.O.C(OCC)(=O)C>CO>[C:3]12([CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:16](=[O:24])[CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)COCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)COCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Next, sodium borohydride (0.18 g, 4.8 mmol) was added to a solution of 2-methoxycarbonylmethoxyacetic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide (0.37 g, 0.96 mmol) in methanol (3 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (10 ml) was added to the reaction mixture, and the whole was stirred for 10 minutes. Then, water (20 ml) and ethyl acetate (30 ml) were added thereto, and layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 74 mg (22%) of 2-(2-hydroxyethoxy)acetic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide as an oily matter.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=2[C:4]#[N:5])=[CH:20][CH:21]=1
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cncc1-c1ccc(N)cc1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
The product from Example 1B (3 g, 17.3 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (4.18 g, 19 mmol), PdCl2dppf.CH2Cl2 (300 mg), and Na2CO3 (4.5 g) were combined in DMF (25 mL) and water (10 mL). The mixture was degassed with nitrogen and heated to 85° C. overnight The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with hexanes:ethyl acetate (1:1) to provide 1.4 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 5.67 (s, 2H) 6.70 (d, J=8.48 Hz, 2H) 7.40 (d, J=8.82 Hz, 2H) 8.76 (s, 1H) 8.79 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].CS(O[CH2:13][CH:14]([N:16]1[C:29]2[CH:28]=[C:27]([C:30]#[N:31])[CH:26]=[CH:25][C:24]=2[S:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])(=O)=O>C(O)C>[OH:7][CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:15][CH:14]([N:16]1[C:29]2[CH:28]=[C:27]([C:30]#[N:31])[CH:26]=[CH:25][C:24]=2[S:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:13]
Reactant: OC[C@H]1CCCN1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCO
Product: CC(CN1CCC[C@@H]1CO)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
(R)-(-)-2-Pyrrolidinylmethanol (50 g) is added to a suspension of (2RS)-2-(2-cyano-10-phenothiazinyl)propyl methanesulphonate (89.1 g) in absolute ethanol (2000 cc). The mixture is brought to reflux for 23 hours. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is diluted with ethyl acetate (350 cc) and filtered, and the filtrate is washed with distilled water (150 cc) and saturated sodium chloride solution (2×100 cc). After settling has taken place, the organic phase is extracted with hydrochloric acid (350 cc) in 3N solution. The acidic aqueous extracts are extracted with ethyl acetate (200 cc) and then alkalinized with concentrated sodium hydroxide and re-extracted with ethyl acetate (3×200 cc). The organic phase is washed with distilled water (2×200 cc) and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is purified by chromatography on a column (height: 46 cm; diameter: 8.5 cm) of silica gel (0.2-0.06 mm), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (12 liters) and 70:30 (30 liters), collecting 250-cc fractions. The first 12 liters are discarded and fractions 61 to 118 are combined and evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbonitrile, L series (11.0 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C[NH2:13].[CH3:14][CH2:15]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:13][CH2:15][CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCO
Reactant: CN
Product: CCNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 15 h

Procedure:
A mixture of 4-bromo-2-fluoro-nitrobenzene (6 g, 27.3 mmol), methylamine (2M in MeOH, 34.1 mL, 68.2 mmol, 2.5 eq) and EtOH (80 mL) is stirred for 15 h at 85° C., allowed to cool and concentrated. The residue purified by trituration to afford 6 g of the title compound as an yellow solid: tR=5.13 min (System 1).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][N:23]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1

Procedure:
To 4-(2-(4-(4-tert-butyldimethylsilyloxybutyl)phenyl)ethoxy)quinazoline (0.4 g, 0.916 mmol) is added tetrabutylammonium fluoride solution (1M TBAF in THF, 4.58 ml, 4.58 mmol). The solution is stirred for 2 hours after which water is added to the reaction and this is extracted in ethyl acetate. The organic layer is then washed with water, dried and concentrated. The residue obtained is purified by flash chromatography (silica gel; ethyl acetate/hexanes)