Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][O:16]2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH:28][C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC1C=CC([C@H](O)CNC2CC3C(=CC(CC)=C(CC)C=3)C2)=C2C=1NC(=O)C=C2)C1C=CC=CC=1>>[CH2:21]([N:28]([C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:17][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)[OH:16])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1cc([C@@H]2CO2)ccc1OCc1ccccc1
Reactant: CC1(NCc2ccccc2)Cc2ccccc2C1
Agent: CCc1cc2c(cc1CC)CC(NC[C@@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Product: CC1(N(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2C1
Reaction time: 24 h

Procedure:
The title compound is prepared from (R)-2-(4-benzyloxy-3-nitro-phenyl)-oxirane (2.52 g) and benzyl-(2-methyl-indan-2-yl)-amine (2.20 g) by an analogous procedure to that used to prepare (S)-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one in Example 19. The reaction is shown to be complete by TLC after 24 hours. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane/ethyl acetate 4:1 Rf=0.30).
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@@H:5]1[OH:11])(C)=[CH2:2].[O:12]=[O+][O-].O=O>C(Cl)Cl.CO>[OH:11][C@H:5]1[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]1[C:1](=[O:12])[CH3:2]
Reactant: C=C(C)[C@H]1CC[C@@H](C)C[C@@H]1O
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)[C@@H]1CC[C@@H](C)C[C@@H]1O
Temperature: 25 °C
Yield: 67 %

Procedure:
To the (1S,2R,5R)-2-Isopropenyl-5-methyl-cyclohexanol (2.07 g, 13.42 mmol) in DCM (67 mL) and MeOH (1.6 mL) at −78° C. was bubbled ozone/oxygen gas until the reaction mixture was turned blue and the excess ozone was flushed off with oxygen, Dimethyl sulfide (4.9 mL) was added at the same temperature, slowly warmed up to room temperature, stirred for over night, concentrated, purified on column chromatography using 10-20% EtOAc/hexane to give (1R,2S,4R)-1-(2-Hydroxy-4-methyl-cyclohexyl)-ethanone (1.40 g, 67%) as an oil. NMR 1H (CDCl3, 400 MHz): 4.29-4.27 ppm (m, 1H); 2.40-2.35 ppm (m, 1H); 2.19 ppm (s, 3H); 1.91-1.73 ppm (m, 5H); 1.05-0.91 ppm (m, 2H); 0.88 ppm (d, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][CH:10]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1)[CH3:11]>C(Cl)(Cl)Cl>[Br:1][C:18]1[N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:20]2[C:16]([N:17]=1)=[C:15]([NH2:28])[N:14]=[C:13]([O:12][CH:10]([CH3:9])[CH3:11])[N:21]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
N-Bromosuccinimide (604 mg, 3.39 mmol) was added to a solution of 2-[(1-methylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (888 mg, 3.20 mmol) in chloroform (30 ml) at 0-5° C. under nitrogen. The mixture was stirred at 0-5° C. for 1 hour during which time it became reddish brown in colour and it was then warmed to room temperature and stirred for a further 4 hours. LCMS indicated the reaction to be incomplete and more N-bromosuccinimide (114 mg, 0.641 mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was then diluted with chloroform (30 ml), washed with water (2×20 ml) and the layers were separated using a hydrophobic frit and the organic layer was evaporated to give a red solid (1.16 g). This material was dissolved in dichloromethane and purified by silica gel chromatography on an SPE cartridge (50 g) using a 0-100% ethyl acetate in cyclohexane gradient as eluent. The appropriate fractions were combined and evaporated to give the title compound as a pale yellow solid 712 mg.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH2:22]([N:29]1[CH2:33][CH2:32][C@H:31](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([N:29]1[CH2:33][CH2:32][C@@H:31]([C:7]([C:8]#[N:9])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a stirred solution of diphenylacetonitrile (12.18 g, 61.8 mmol) in anhydrous THF (120 mL) at 0° C., potassium tert-butoxide (10.60 g, 94.6 mmol) was added over 5 min. The mixture was stirred at 0° C. for 1 hour. To the mixture at 0° C. was added intermediate (1a) (20.48 g, 61.3 mmol) in one portion. The cold bath was removed and the mixture was stirred for 5-10 minutes at which time the mixture had become a brown homogeneous solution. The mixture was then heated at 40° C. overnight (20±5 hours). The mixture (bright yellow suspension) was allowed to cool to ambient temperature before adding water (150 mL). Most of the THF was then removed in vacuo and IPAc (200 mL) was added. The layers were separated and the organic layer was washed with saturated aqueous NH4Cl solution (150 mL); saturated aqueous NaCl solution (150 mL); and then dried over sodium sulfate (50 g). The sodium sulfate was filtered off and washed with IPAc (20 mL) and the solvent was removed in vacuo to give 23.88 g of intermediate (1b) as a light brown oil (>99% yield). Intermediate (1b) was determined to have a purity of 75% (contaminated mainly with excess diphenylacetonitrile) using the HPLC method described above.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](#[N:12])[CH:10]=[CH2:11]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[I:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:10][C:9]#[N:12])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC#N
Reactant: Nc1cccc(I)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: N#CCCNc1cccc(I)c1
Yield: 37 %

Procedure:
13at) 4.38 g of 3-iodoaniline, 1.06 g of acrylonitrile and 0.5 g of copper-(II)acetate are mixed and held at 70° for 5 hrs. The mixture is chromatographed on silica gel with ethyl acetate/cyclohexane 1:4 and yields 2.01 g of 3-(3-iodo-phenylamino)-propionitrile as a brown oil. Yield: 37%. Mass spectrum: peak inter alia at m/e : 272 (M+, 50%), 232 (100%); 105 (35%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C:10]1[CH:15]=[C:14]([NH:16][C:17](=[O:33])[CH2:18][C:19](=[O:32])[CH2:20][O:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)[CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N:36]([O-])=[O:37].[Na+]>C(O)(=O)C.C1COCC1>[CH2:1]([O:8][C:9](=[O:34])[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17](=[O:33])[C:18](=[N:36][OH:37])[C:19](=[O:32])[CH2:20][O:21][C:22]23[CH2:29][CH:28]4[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]4)[CH2:23]2)[CH2:31]3)[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(COC12CC3CC(CC(C3)C1)C2)C(=NO)C(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution of the product of step b (2.10 g, 4.55 mmol) in acetic acid (20 ml) and THF (20 ml) was added water (2 ml). The mixture was cooled to 5° C. and an aqueous solution (3 ml) of sodium nitrite (0.41 g, 5.92 mmol) was added dropwise while maintaining the temperature below 10° C. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The THF and acetic acid were removed in vacuo and the solution was partitioned between water (100 ml) and ethyl acetate (100 ml). 1M NaOH was added until pH 8 was reached, the layers were separated, and the aqueous layer was washed with ethyl acetate (20 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and the solvent was evaporated to yield a yellow oil (2.13 g, 96%). The crude product was purified by flash column chromatography (silica, DCM/ethyl acetate 95:5) to afford a yellow foam (1.29 g, 58%). 1H NMR (300 MHz, CDCl3) 11.04 (1H, br s), 8.23 (1H, s), 7.94 (1H, d), 7.86 (1H, d), 7.50-7.36 (6H, m), 5.39 (2H, s), 4.82 (2H, s), 2.20 (3H, br s), 1.81 (6H, s), 1.65 (6H, m).
Reaction SMILES: [O:1]1[C@@:15]23[C@:6]4([CH2:18][CH2:17][N:16](C(=O)C(F)(F)F)[C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:25][CH3:26])=[CH:8][C:7]4=2)[CH2:5][CH2:4][CH2:3][CH:2]13.[BH4-].[Na+].Cl>C(O)C>[O:1]1[C@@:15]23[C@:6]4([CH2:18][CH2:17][NH:16][C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:25][CH3:26])=[CH:8][C:7]4=2)[CH2:5][CH2:4][CH2:3][CH:2]13
Reactant: COc1ccc2c(c1)[C@@]13CCCC4O[C@@]41[C@@H](C2)N(C(=O)C(F)(F)F)CC3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)[C@@]13CCCC4O[C@@]41[C@@H](C2)NCC3

Procedure:
A mixture of 1.0 g. (2.72 mmole) of the epoxide XXI and 0.103 g. (2.72 mmole) of sodium borohydride in 5 ml. of absolute ethanol was refluxed during 5 minutes. After cooling, the reaction mixture was acidified with dilute hydrochloric acid and then extracted with ether. The aqueous layer was separated and made alkaline by the addition of aqueous ammonia and then extracted with methylene chloride. The resulting extracts were dried over Na2SO4 and concentrated in vacuo to yield 800 mg. of an oil (XXII) which was not further purified but used directly in the next transformation. The IR and NMR spectra were consistent with the structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19](=[S:21])[NH2:20]>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:20]=[C:19]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:13]=2[CH3:12])[S:21][CH:2]=1
Reactant: Cc1ccncc1C(N)=S
Reactant: Cc1ccncc1C(=O)CBr
Product: Cc1ccncc1-c1csc(-c2cnccc2C)n1
Yield: 42 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (392 mg) and 4-methylpyridine-3-thiocarboxamide (152 mg), the title compound (112 mg) was obtained as colorless powder crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36](O)=[O:37])[CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:28]4[CH:27]=[N:26][C:35]5[C:30]([CH:29]=4)=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cnc5ccccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-3-carboxylic acid as starting compounds.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][C:27]=1[Cl:28])/[CH:17]=[N:18]/S(C(C)(C)C)=O.Cl>CCOCC.CO.C1COCC1>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[NH2:18])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: Ic1ccccn1
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: NC(c1ccc(Cl)c(Cl)c1)c1ccccn1
Temperature: -100 °C
Reaction time: 0.25 h

Procedure:
A 250-mL round-bottomed flask was charged with 2-iodopyridine (1.0 g, 4.88 mmol) and 50 mL of THF. The resulting mixture was cooled to −100° C. and then n-BuLi (2.5 M in hexanes, 5.3 mL, 13 mmol) was added at such a rate that the internal temp did not rise above −97° C. After 15 min at −100° C., (E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide (1.36 g, 4.88 mmol) was added and stirring was continued for 1 h at −100° C. 30 mL of 1M HCl in ether was added, and the mixture was allowed to warm to rt. Once at rt, 5 mL of MeOH was added and the mixture was stirred for an additional 1 h. The resulting precipitate was collected by filtration to give (3,4-dichlorophenyl)(pyridin-2-yl)-methanamine hydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=O)[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[S:30])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Solvent: Cc1ccccc1
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(Br)c3)cc21
Temperature: 110 °C
Yield: 122.9 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (3 g, 9.04 mmol) and Lawesson's Reagent (1.83 g, 4.51 mmol) in toluene (30 mL) was heated to 110° C. for 24 hours. The reaction was cooled, the toluene removed in vacuo and the residue purified via flash chromatography (silica gel, 20% ethyl acetate/hexane) to give 6-(3-bromophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione (1.93 g, 61%) as a yellow solid: mp 191-193° C.; 1H-NMR (DMSO-d6) (12.3 (s, 1H), 7.92 (s, 1H), 7.72-7.65 (m, 3H), 7.57-7.54 (m, 1H); 7.45-7.39 (m, 1H), 7.14-7.11 (m, 1H), 1.7 (s, 6H); MS (ES) m/z 347 ([M−H]−, 100%); Anal. Calcd. For C16H14BrNOS: C, 55.18; H, 4.05; N, 4.02 Found: C, 55.17; H, 3.93; N, 3.97.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[N:18](C(=O)C)[N:19]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:21]=1)=[O:15])[CH3:3].CC(C1C=CC=C(C(C)C)C=1NC(NC1N(C(=O)C)N=C(CCCCCCCCCCC)N=1)=O)C>>[CH3:12][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[N:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[NH:19][N:18]=1)=[O:15])[CH3:11]
Reactant: CCCCCCCCCCCCc1nc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n(C(C)=O)n1
Agent: CCCCCCCCCCCc1nc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n(C(C)=O)n1
Product: CCCCCCCCCCCCc1nc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n[nH]1

Procedure:
Employing the general method of Example 2 but using N-[2,6-bis(1-methylethyl)phenyl]-N'-(2-acetyl-5-dodecyl-2H-1,2,4-triazol-3-yl)urea instead of N-[2,6-bis(1-methylethyl)phenyl-N'-(2-acetyl-5-undecyl-2H-1,2,4-triazol-3-yl)urea, the title compound was prepared; m.p. 154°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.[Mg].[C:11]([CH:13]1[CH2:15][CH:14]1[C:16](N(OC)C)=[O:17])#[N:12].[Cl-].[NH4+]>BrC(Br)C.C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:16]([CH:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[O:17]
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: Fc1ccc(Br)c(F)c1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC1CC1C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, a few drops of dibromoethane and then 5.00 g (25.9 mmol) of 2,4-difluorobromobenzene, dissolved in 50 ml of diethyl ether, were added to 661 mg (27.2 mmol) of magnesium in 100 ml of dry diethyl ether. The mixture was heated under reflux for 2 h. After cooling, the supernatant reaction solution was added dropwise under argon to a solution of 3.63 g (23.5 mmol) of the compound from Example 73A in 80 ml of THF, and the mixture was stirred at RT overnight. The reaction solution was then added to saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) resulted in 2.15 g (44% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1cc(I)ccc1OC
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(N2CCOCC2)ccc1OC
Temperature: 100 °C
Yield: 39.8 %

Procedure:
5-Iodo-2-methoxy-benzoic acid methyl ester (500 mg, 1.7 mmol), morpholine (223 μl, 2.5 mmol), cesium carbonate (850 mg, 2.7 mmol), xantphos (60 mg, 0.1 mmol) and bis(dibenzylideneacetone)dipalladium (35 mg, 0.04 mmol) were suspended in dioxane (5 ml) and heated at 100° C. for 5 h. The mixture was then cooled, filtered and the residue was purified by flash column chromatography [SiO2, EtOAc] to give 2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (170 mg) as a colourless solid. (LC/MS (basic method): Rt 2.35 min, [M+H]+ 252).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2>O>[F:32][C:30]([F:31])([F:33])[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:22][CH:21]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(Cc3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2
Solvent: O
Product: O=C(O)COc1ccc(SCc2ccc(Cc3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 40D. IR cm−1:1745, 1704, 1325; 400 MHz 1H NMR (DMSO-d6) δ 7.58 (d, 2H, J=8.1 Hz), 7.37 (d, 2H, J=8.1 Hz), 7.09 (s, 2H), 7.05 (d, 2H, J=8.3 Hz), 6.55 (d, 1H, J=8.3 Hz), 4.60 (s, 2H), 3.94 (s, 4H), 2.71 (t, 2H, J=8.3 Hz), 2.58 (t, 2H, J=8.3 Hz), 1.81 (m, 2H); MS m/z 473 (M+1). Anal. Calc'd for C26H23F3O3S.0.1 H2O, C, 65.84; H, 4.93. found: C, 65.58; H, 4.96.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]>CO.O>[NH2:18][C:15]1[CH:14]=[CH:13][C:12](/[N:11]=[N:10]/[C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: CCN(CC)c1ccc(/N=N/c2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Solvent: CO
Product: CCN(CC)c1ccc(/N=N/c2ccc(N)cc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
56.7 g of N,N-diethyl-4-[(E)-(4-nitrophenyl)diazenyl]aniline (0.19 M) were slurried in 270 ml of methanol at 60° C. and a solution of 147 g of sodium hydrogen sulfide-1-hydrate (1.98 M) in 150 ml of water was added cautiously. Upon addition, the former thick suspension became more liquid and the reaction mixture boiled heavily. When addition was complete, it was stirred for 0.5 h at 60° C., then cooled to room temperature and 400 ml of ice-water were added. The resulting suspension was stirred for 10 min., thereafter the solids were filtered off and washed several times with warm water, giving almost pure N-{4-[(E)-(4-aminophenyl)diazenyl]phenyl}-N,N-diethylamine as red-orange solid, used without drying in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[CH2:31][C:17]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]2[N:24]([C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20]2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cc3c(F)cccc3Cl)c(-c3ccccc3)c3ccccn23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1c(Cc2c(F)cccc2Cl)c(-c2ccccc2)c2ccccn12)N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
The compound of step 3 (0.886 g, 1.62 mmol) was dissolved in DCM (6.5 ml). The solution was cooled at 0° C. and a 4 N solution of hydrogen chloride in dioxane (2.02 ml, 8.08 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated to dryness. The residue was triturated several times with diethyl ether, filtered, rinsed with diethyl ether and dried in a vacuo at 65° C. to give 0.70 g of the title compound in the form of [2-(2-chloro-6-fluoro-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][C:18]#[CH:19]>>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[O:20]
Reactant: C#CCCCCO
Reactant: COc1ccc2nccc(Br)c2n1
Product: COc1ccc2nccc(CCCCCC=O)c2n1
Yield: 42 %

Procedure:
The title intermediate was obtained starting from 8-bromo-2-methoxy-[1,5]naphthyridine (4 g, 16.7 mmol) and hex-5-yn-1-ol (2.7 g, 1.65 eq.) and following the procedures of Example 29, step 29.i and Example 33, steps 33.i and 33.ii. The title aldehyde was isolated as a yellowish liquid (1.2 g, 42% yield over 3 steps).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.[NH2:13][OH:14].C1(C)C=CC=CC=1>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:13]\[OH:14])/[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C/C(=N/O)c1ccc(O)cc1O
Temperature: 25 °C
Yield: 97 %

Procedure:
1-(2,4-dihydroxyphenyl)ethanone (4.5 g, 29.6 mmol) was dissolved in pyridin (17 mL). Hydroxylamine hydrochloride (2.1 g, 29.6 mmol) was added in small portions over 10 minutes. After stirring at room temperature over night the green-yellowish solution was partitioned between water and ethyl acetate. The organic phase was washed twice with water and once with 0.2 M hydrochloric acid, and was finally concentrated. The oily residue was treated with water, evaporated to yield a white semi solid residue, which was treated with toluene and evaporated to give the titled compound (4.8 g, 98%) as a white solid.