Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][CH:29]([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][CH:29]([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)CC(=O)O
Agent: Cl
Product: CC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (8.2 mg, 28%), MS (ISP) m/z=416.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3-methylbutanoic acid.
Reaction SMILES: ClCCCCC(OCC)CC.[CH2:12]([O:14][CH:15]([CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]=[CH:21]1)[CH3:13].[Cl:27][C:28]1([Cl:46])[C:34](=[O:35])[CH:33]2C1CCC2CCCCC(OCC)CC.[N+](=C)=[N-]>>[Cl:27][C:28]1([Cl:46])[C:34](=[O:35])[CH2:33][CH:24]2[CH:23]1[CH2:22][CH2:21][CH:20]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([O:14][CH2:12][CH3:13])[CH2:25][CH3:26]
Reactant: CCOC(CC)CCCCC1C=CCC1
Reactant: CCOC(CC)CCCCC1CCC2C1C(=O)C2(Cl)Cl
Agent: C=[N+]=[N-]
Agent: CCOC(CC)CCCCCl
Product: CCOC(CC)CCCCC1CCC2C1CC(=O)C2(Cl)Cl

Procedure:
The corresponding 2-(5-ethoxyhept-1-yl) homologs are prepared by substituting an equivalent amount of 1-chloro-5-ethoxyheptane in the Grignard reaction of Example 1 in place of the 5-methoxy homolog and using the reaction sequence shown above to prepare first the 3-(5-ethoxyhept-1-yl)cyclopentene, which is then converted to the 6,6-dichloro-2-(5-ethoxyhept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-(5-ethoxyheptyl)bicyclo[3.2.0]heptan-6-one} of this invention. The diazomethane reaction described for the methoxy homolog produces the 6,6-dichloro-2-(5-ethoxyhept-1yl) bicyclo[3.3.0]octan-7-one {7,7-dichloro-4-(5-ethoxyheptyl)bicyclo[3.2.0]heptan-6-one}.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C@@H:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]1[OH:28]>O1CCCC1>[CH:8]1([C:11]([NH:14][C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][C@H:16]2[OH:28])=[O:12])[CH2:10][CH2:9]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (4.85 mL, 34.8 mmol) and cyclopropanecarbonyl chloride (3.18 mL, 35.0 mmol) were added to a 0° C. solution of tert-butyl trans-4-amino-3-hydroxypiperidine-1-carboxylate (7.52 g, 34.8 mmol) in tetrahydrofuran (100 mL), and the reaction was allowed to warm to room temperature and stir for 18 hours. After concentration in vacuo, the crude product was diluted with ethyl acetate, insoluble material was removed by filtration, and the solids were washed with ethyl acetate (3×50 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in ethyl acetate) to afford the product as a solid. Yield: 1.30 g, 4.57 mmol, 13%. LCMS m/z 285.6 [M+H]+. 1H NMR (400 MHz, CDCl3), observed peaks: δ 5.79 (br d, J=5 Hz, 1H), 4.21-4.34 (br m, 1H), 4.03-4.21 (br m, 1H), 3.70-3.79 (m, 1H), 3.34-3.42 (m, 1H), 2.66-2.79 (br m, 1H), 2.59 (br dd, J=12, 11 Hz, 1H), 1.88-1.96 (m, 1H), 1.46 (s, 9H), 1.37-1.44 (m, 1H), 1.01-1.05 (m, 2H), 0.77-0.87 (m, 2H).
Reaction SMILES: [N:1]([CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[N:7][N:6]([CH3:15])[C:5]1=[O:16])=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[N:7][N:6]([CH3:15])[C:5]1=[O:16]
Reactant: CN1N=Cc2ccccc2C(N=[N+]=[N-])C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1N=Cc2ccccc2C(N)C1=O
Reaction time: 1 h

Procedure:
To a solution of 5(R,S)-azido-4,5-dihydro-3-methyl-3H-2,3-benzodiazepin-4-one (1.5 g, 7 mmol) in EtOAc (150 mL) was added 10% Pd on carbon (50 mg) and stirred under an atmosphere of hydrogen. The reaction was closely monitored by TLC using EtOAc as eluent. The reaction was complete after 1 h (TLC) and then filtered the catalyst over a pad of celite. The solvent was removed and the 5(R,S)-amino-4,5-dihydro-3-methyl-3H-2,3-benzodiazepin-4-one was dried under high vacuum. This amine product was used immediately in the coupling reactions with various amino acids to yield Formula IIC products.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:23])=[C:6]([S:8]([N:11]([CH2:19][O:20][CH2:21][CH3:22])[C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[OH:39])[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[NH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[O:39][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([N:11]([CH2:19][O:20][CH2:21][CH3:22])[C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)(=[O:10])=[O:9])=[C:5]([F:23])[CH:4]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Temperature: 50 °C
Reaction time: 19 h
Yield: 58.4 %

Procedure:
To a solution of 5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 14, 75 mg, 0.20 mmol) in dimethylsulfoxide (1 mL) was added 2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 13, 43.3 mg, 0.20 mmol) and potassium carbonate (40.7 mg, 0.30 mmol). The reaction mixture was stirred at 50° C. for 19 hours, then diluted with ethyl acetate (30 mL) and washed with 1N aqueous sodium hydroxide solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% hexanes in ethyl acetate to 100% ethyl acetate gradient elution) to afford the title compound as a white solid (68 mg).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].[CH:28](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[CH:28]=[N:12][N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(OCC)OCC
Product: CCCc1nc(C)n2cnnc2c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
20 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, are heated to reflux for 6 hours in 200 ml of triethyl orthoformate. The mixture is then concentrated under vacuum and the residue is taken up with ether. The crystals obtained are drained and washed with ether to give 18.8 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[4,3-c]pyrimidine in the form of crystals of melting point 153° C.
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(NC(=O)C5C=CC(C(O)(C)C)=CC=5F)C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[CH3:60][N:61]([CH3:87])[C:62]([N:64]1[CH2:69][CH:68]=[C:67]([C:70]2[NH:86][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[CH:82][C:81]([F:84])=[C:80]([NH2:85])[CH:79]=4)[C:72]=3[CH:71]=2)[CH2:66][CH2:65]1)=[O:63].FC1C=C(C(O)(C)C)C=CC=1C(O)=O.[OH:102][CH2:103][C:104]([C:107]1[CH:115]=[CH:114][C:110]([C:111](O)=[O:112])=[CH:109][CH:108]=1)([CH3:106])[CH3:105]>>[CH3:60][N:61]([CH3:87])[C:62]([N:64]1[CH2:65][CH:66]=[C:67]([C:70]2[NH:86][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[CH:82][C:81]([F:84])=[C:80]([NH:85][C:111](=[O:112])[C:110]5[CH:114]=[CH:115][C:107]([C:104]([CH3:105])([CH3:106])[CH2:103][OH:102])=[CH:108][CH:109]=5)[CH:79]=4)[C:72]=3[CH:71]=2)[CH2:68][CH2:69]1)=[O:63]
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(N)c4)ncnc3[nH]2)CC1
Reactant: CC(C)(CO)c1ccc(C(=O)O)cc1
Agent: CC(C)(O)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(NC(=O)c5ccc(C(C)(C)CO)cc5)c4)ncnc3[nH]2)CC1

Procedure:
Example 21 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 10 and Intermediate 8 with 4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[C:4](Cl)[N:3]=1.CS(C)=O.[NH3:19]>C(OCC)(=O)C>[NH2:19][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]=1[O:12][CH3:13]
Reactant: N
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1OC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1nc(Cl)nc(N)c1OC
Temperature: 2.5 °C
Reaction time: 0.21 h
Yield: 50 %

Procedure:
A solution comprising the reaction mixture prepared by Example 8, which reaction mixture contained the methyl 2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate (25 g, 0.1 mol), and dimethyl sulfoxide (DMSO) was prepared. To this solution was added, at 0-5° C., a solution of ammonia in DMSO (2 eq). This mixture was stirred at the same 0-5° C. temperature for 10 to 15 minutes. Later, the mixture was diluted with ethyl acetate, and the resulting solid was filtered. The filtrate was washed with a brine solution. The organic layer was dried over sodium sulfate. Upon concentration, the crude product was obtained. The crude product was stirred in a minimum amount of ethyl acetate and filtered to obtain the pure compound. The resulting filtrate, after concentration, was column purified. This produced the title compound (11 g, 50% yield): mp 158° C.; 1H NMR (DMSO-d6) δ 3.71 (s, 3H), 3.86 (s, 3H), 7.65 (brs, 1H), 8.01 (brs, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Mg]Br>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Reactant: Br[Mg]c1cccs1
Solvent: C1CCOC1
Product: OC(c1cccc(OCCCCCCCCC2OCCO2)c1)c1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde (1.0 g, 3.25 mmol) in THF (30 mL) at −78° C. under an atmosphere of nitrogen, a solution of 2-thienylmagnesium bromide (1M in THF, 4.23 mL, 4.23 mmol) was added over 10 minutes. After stirring at −78° C. for 1 hour, the reaction was allowed to warm to RT and stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in iso-hexane to afford the title compound (1.12 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[C:23]4[C:22]([NH:24][C@H:25]([C:27]5[N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:31](=[O:39])[C:30]6=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]6[N:28]=5)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=4[N:17]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:16]=3)=[N:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)CC)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>N1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([NH:1][S:60]([CH3:59])(=[O:62])=[O:61])[CH:3]=[C:4]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[C:23]4[C:22]([NH:24][C@H:25]([C:27]5[N:32]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:31](=[O:39])[C:30]6=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]6[N:28]=5)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=4[N:17]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:49])[CH3:50])[CH:16]=3)=[N:11]2)[CH:5]=1
Reactant: COc1cc(N)cc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1cc(NS(C)(=O)=O)cc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
(S)-2-(1-((5-(1-(3-Amino-5-methoxyphenyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (15.3 mg, 0.02 mol) was dissolved in 2 ml pyridine and triethylamine (5 μl, 0.04 mol). The mixture was submitted to three vacuum-argon cycles and was cooled at 0° C. with an ice bath. Methanesulfonyl chloride (2 μl, 0.03 mol) was added dropwise and the reaction mixture was stirred for 2 h. The solvent was concentrated and the residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure, to obtain 16.6 mg (94% yield) of the title compound. Purity 72%.
Reaction SMILES: Br[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[C:7]([O:8][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)(=[O:6])[CH3:9]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CBr)OC(C)(C)O1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Solid tetrabutylammonium acetate (62.1 g, 0.207 mole, commercially available reagent was used) was added in one portion to a stirring solution of the bromoacetonide obtained in step (c) above (22.3 g, 0.068 mole) in 1-methyl-2-pyrrolidinone (276 ml, commercially available HPLC grade, used as purchased) under an argon atmosphere. The resulting solution was stirred at 90° C. (external temperature) for 1 hour (after a few minutes the reaction mixture became brown in color) to complete the reaction. (The progress of the reaction was followed by TLC, Rf =0.48 for the title product; Rf =0.63 for the bromoacetonide starting material (Silica gel, Ethyl acetate:Hexane, 1:1, visualization by Ce(SO4)2 spray).) The reaction mixture was cooled to room temperature and poured into water (1.5 L) and extracted with heptane (4×800 ml). The organic layers were combined and washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure to furnish 18.45 grams of a brown solid. It was dissolved in heptane (250 ml) and treated with neutral NORIT® (25 grams).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH:12]=O)[NH:9]2)=[CH:5][CH:4]=1.[Br-].[CH2:15]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH:12]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(C=O)[nH]c2c1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: COc1ccc2cc(C=Cc3ccccc3)[nH]c2c1
Yield: 94 %

Procedure:
Reaction of 6-methoxyindole-2-carboxaldehyde (145) with benzyltriphenylphosphonium bromide using the procedure described in example 37 gave (146) (94%) as a white solid (mixture of E/Z isomers) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:22]=[C:23]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:24]=[C:25]([Cl:28])[C:26]=1[Cl:27].C(=O)([O-])O.[K+]>COCCOC.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:30][C:29]([C:23]3[CH:24]=[C:25]([Cl:28])[C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)([C:31]([F:34])([F:33])[F:32])[O:7][N:6]=2)[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C=NO)cc1Cl
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10.5 g of 3-chloro-4-methylbenzaldoxime in 50 mL of 1,2-dimethoxyethane, 9.1 g of N-chlorosuccinimide was added and the resultant mixture was stirred at 70° C. for 2 hours. Next, the reaction mixture was left to be cooled down to room temperature and to the reaction mixture, 17.0 g of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 9.3 g of potassium hydrogen carbonate and 10 mL of water were added, followed by continuing the stirring of the reaction mixture at room temperature further for 16 hours. After the completion of the reaction, the reaction mixture was diluted with 200 mL of ethyl acetate, and the diluted reaction mixture was washed with water (70 mL×1). Subsequently, the washed reaction mixture was dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:5) to obtain 26.2 g of the objective substance as a brown resinoid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][OH:14]>>[CH2:5]([O:4][C:2](=[O:3])[NH:13][OH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Product: O=C(NO)OCc1ccccc1

Procedure:
170.5 parts of benzyl chloroformate are reacted with 69.5 parts of ground hydroxylamine hydrochloride in a similar manner to Example 8 to give 149 parts of benzyl-N-hydroxycarbamate as a waxy solid.
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=4[Cl:68])[C:62](O)=[O:63])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1>C1COCC1.O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([C:62]([N:5]5[CH2:6][C:3]([F:7])([F:2])[CH2:4]5)=[O:63])[CH:65]=[CH:66][C:67]=4[Cl:68])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)N2CC(F)(F)C2)ccc1Cl
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a mixture of 3,3-difluoroazetidine hydrochloride (1.18 g, 9.13 mmol), DIPEA (5 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3.00 g, 6.09 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred for 5 h, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo to give 8-bromo-N-(2-chloro-5-(3,3-difluoroazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (3.2 g, yield 93%). 1H NMR (DMSO, 400 MHz): δ7.56-6.59 (m, 7H, ArH), 4.76-4.48 (m, 4H, 2CH2), 4.31 (t, J=5.2 Hz, 2H, CH2), 3.33 (s, 3H, CH3), 2.96 (t, J=5.2 Hz, 2H, CH2)
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]([CH3:5])[CH3:4].C(Br)CC(C)C.[Mg].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@@H:22]1[C@@:42]2([CH3:43])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[CH:34]([CH:36]=[O:37])[CH3:35])[CH2:25][C@@H:24]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:23]1.[OH-].[Na+]>O1CCCC1>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:21][C@@H:22]1[C@@:42]2([CH3:43])[C:26](=[CH:27][CH:28]=[C:29]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[C@H:34]([CH3:35])[CH:36]([OH:37])[CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:25][C@@H:24]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:23]1
Reactant: CC(C)CC[Mg]Br
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Mg]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)CCBr
Product: CC(C)CCC(O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To 20 ml of a tetrahydrofuran solution of the isoamylmagnesium bromide prepared from 2.27 g of isoamyl bromide and 0.48 g of magnesium was slowly added a solution of 5.12 g of 1α,3β-bis(tetrahydropyran-2-yloxy)pregna-5,7-diene-20-carbaldehyde in 30 ml of tetrahydrofuran under ice-cooling. After the addition, the mixture was further stirred at 0° C. for 1 hour. To the reaction mixture thus obtained was added 2N aqueous sodium hydroxide solution, followed by extraction with diethyl ether. The extract was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 4.84 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol (yield: 83%) showing the following physical property.
Reaction SMILES: CS[C:3]1[N:4]=[CH:5][C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>CO.O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:3]1[N:4]=[CH:5][C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: NCc1ccccc1Cl
Reactant: CSc1ncc2c(=O)[nH]ccc2n1
Solvent: O
Solvent: CO
Product: O=c1[nH]ccc2nc(NCc3ccccc3Cl)ncc12
Reaction time: 8 h
Yield: 90.3 %

Procedure:
2-Methylsulfanyl-6H-pyrido[4,3-d]pyrimidin-5-one 6 (3.00 g, 15.5 mmol) and 2-Chlorobenzyl amine 7 (9.40 mL, 77.6 mmol) were stirred at 150° C. for two days. To the recooled mixture Methanol/water (1:1, 100 mL) was added and left at RT overnight. The precipitate was filtered off and dried in vacuo. The product was purified by crystallization from ethanol to yield in a colorless solid (4.00 g, 14.0 mmol, 90%).