Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[CH2:11][CH2:10]3)[CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[S:27])[CH2:11][CH2:10]3)[CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2cc(-c3cccnc3)ccc2N1
Solvent: Cc1ccccc1
Product: S=C1CCc2cc(-c3cccnc3)ccc2N1
Temperature: 25 °C

Procedure:
To the title compound from Example 1 Step A (200 mg, 0.892 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (180 mg, 0.446 mmol) was added toluene (1.8 mL). The suspension was heated to reflux for 45 minutes. The reaction was then cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% methanol in ethyl acetate) provided the title compound: LCMS m/z 241.22 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.86 (d, J=2.0 Hz, 1H), 8.55 (dd, J=1.5, 4.8 Hz, 1H), 8.11 (ddd, J=1.9, 2.2, 8.2 Hz, 1H), 7.61-7.58 (m, 2H), 7.53 (dd, J=4.9, 8.0 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 3.09-3.06 (m, 2H), 2.99-2.96 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:29][CH2:28]4)=[C:23]([NH2:26])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:38]#[N:39])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.C(N(CC)C1C=CC=CC=1)C.[C:51](Cl)(=[O:53])[CH3:52]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:27]4[CH2:28][CH2:29][CH:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:31][CH2:32]4)=[C:23]([NH:26][C:51](=[O:53])[CH3:52])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:38]#[N:39])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(N)cc23)cc1Cl
Reactant: CC(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)Nc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Yield: 87.8 %

Procedure:
By the procedure of Example 27, 0.1 g (0.18 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-amino-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile is reacted with 0.3 ml (1.9 mmol) of N,N-diethyl aniline and 0.04 ml (0.56 mmol) of acetyl chloride in 1.5 mL of NMP. The crude residue is purified by silica gel chromatography (gradient 95:5 methylene chloride/methanol to 4:1 methylene chloride/methanol) to give 95 mg of N-[4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-3-cyano-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinolin-6-yl]acetamide as a beige solid, mp 243-255° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[N+]=[N-].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:34]([O:33][C:31]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:5]1[CH2:4][NH2:1])=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccccc1

Procedure:
(2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine and benzyl chloroformate/N-ethyldiisopropylamine in CH2Cl2 (see cabamate synthesis, Method A)—followed by Staudinger reduction gave (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid benzyl ester as white foam, MS: 509 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16]CCO)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:51][CH2:52][N:53]([CH:57](C)C)[CH:54](C)C.CS(Cl)(=O)=[O:62].O>C(Cl)Cl>[CH:35]([OH:34])=[O:62].[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][N:13]([CH2:51][CH2:52][N:53]([CH3:57])[CH3:54])[C:12](=[O:16])[CH:11]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(OCCO)c4)c4ccccc43)cn12
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccn(CCN(C)C)c(=O)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Intermediate 67e (86 mg, 0.13 mmol) and DIPEA (49 mg, 65 μL) were suspended in DCM (5 mL) and methanesulfonyl chloride (19 mg, 13 μL, 0.16 mmol) was added, and the reaction was stirred at room temp. After 30 min, H2O (5 mL) and DCM (5 mL) was added, stirred, and passed through a phase separator cartridge and the organics concentrated in vacuo. The resulting residue was then suspended in dimethylamine solution (2M in THF, 2.5 mL) in a microwave vial, sealed with a crimped septum and stirred at 60° C. The reaction was then cooled, concentrated in vacuo, subjected to FCC, eluting with 0-7% 2M NH3 in MeOH/DCM, then purified further by HPLC (Gemini C18, 10-98% MeCN in H2O, 0.1% HCO2H, 20 min gradient, 18 mL/min) and the combined fractions freeze dried to afford the title compound (22 mg, 24%). LCMS (Method 5): Rt 3.55 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.2 Hz), 1.27 (9H, s), 1.46-1.54 (2H, m), 1.61-1.73 (2H, m), 1.75-1.87 (2H, m), 1.89-1.97 (2H, m), 1.99-2.10 (1H, m), 2.17 (6H, s), 2.15-2.22 (2H, m), 2.87-2.95 (1H, m), 3.13-3.20 (1H, dt, J=12.0, 4.5 Hz), 3.32 (2H, m, obscured by water), 3.98 (2H, t, J=6.2 Hz), 4.83 (1H, q, J=7.9 Hz), 5.53 (1H, t, J=4.1 Hz), 6.37 (1H, s), 6.54-6.56 (1H, m), 6.57-6.61 (1H, dd, J=7.4, 2.4 Hz), 7.18-7.23 (1H, dd, J=2.3, 9.9 Hz), 7.24-7.32 (2H, m), 7.35-7.40 (3H, m), 7.64 (1H, dd, J=0.8, 9.8 Hz), 7.70-7.72 (1H, m), 7.73 (1H, d, J=7.5 Hz), 8.22 (0.25H, s), 8.35 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][CH2:14][C:15](=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:22][C:23]([CH3:31])=[CH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>>[F:13][CH2:14][C:15]1[NH:22][C:23]([CH3:31])=[C:24]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[CH3:1])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(N)=CC(=O)OC(C)C
Reactant: Cc1c(C=O)cccc1[N+](=O)[O-]
Reactant: COC(=O)CC(=O)CF
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
2-Methyl-3-nitrobenzaldehyde (1.23 g, 7.5 mmoles), methyl 4-fluoro-3-oxobutanoate (1.0 g, 7.5 mmoles) and 1-methylethyl 3-amino-2-butenoate (1.07 g, 7.5 mmoles) were heated with stirring at 80° for 2.5 hours. The cooled residue was chromatographed twice on silica eluting first with ethyl acetate/petroleum ether (60°-80°) and then with ethyl acetate/methylene chloride. The title compound (0.61 g) was obtained by crystallisation from a mixture of petroleum ether (60°-80°) and 2-propanol mp 132°-133°.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH2:37][OH:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[OH:38][CH2:37][C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:24][CH2:25]2)[CH:4]=1
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added (2R)-2-pyrrolidinylmethanol (101.15 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 0.54 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.5 mg of the title compound (69.7%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=C(C=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[C:61]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[S:69](Cl)(=[O:71])=[O:70])#[N:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:3]([CH:2]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([S:69]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=2[C:61]#[N:62])(=[O:71])=[O:70])[CH2:58][CH2:59]1
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as the starting materials in 60% yield. LCMS for C31H32ClN8O2S (M+H)+: m/z=615.2.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[O:14]C=CC=2)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:23].[K+].CC(O)C>CC(C)=O.O>[CH2:1]([N:8]1[C:12]([C:13]([OH:14])=[O:23])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: FC(F)(F)c1cc(-c2ccco2)n(Cc2ccccc2)n1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C(O)c1cc(C(F)(F)F)nn1Cc1ccccc1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
To a solution of 9.5 g (0.0325 mol) 1-benzyl-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole in 350 mL acetone was added 27.2 g (0.172 mol) potassium permanganate in 450 ml water. The reaction mixture was heated at 60° C. for 4 h. After cooling to room temperature 200 ml 2-propanol were added and the mixture was stirred over night, it was filtered through a Celite pad and washed with 1 l acetone. The filtrate was concentrated in vacuo down to 150 mL. The residue was dissolved in 20 mL 2M NaOH and 150 mL water. The resulting aqueous phase was washed twice with 70 ml ethyl ether and was then acidified with 30 ml 5M HCl solution. The suspension was extracted with 200 and 50 ml ethyl acetate (EtOAc). The combined organic extracts were washed with 30 mL water and 5 mL brine and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 with 1% acetic acid) to give 6.1 g (0.022 mol, 67%) of 2-benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid as a off-white solid. MS: M=271.1 (ESI+)
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:9]([O:11]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:27][S:28]([CH2:31][C:32]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12)=[O:33])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12

Procedure:
A solution of benzhydryl 7-amino-3-cephem-4-carboxylate (0.78 g, 2 mmol), methylsulfonylacetic acid (0.27 g, 2 mmol), and dicyclohexylcarbodiimide (0.4 g, 2 mmol) in dry tetrahydrofuran (15 ml) is stirred at room temperature overnight. The precipitate is collected and washed with tetrahydrofuran and the combined filtrate and washings are evaporated in vacuo. The residue is treated with a cold solution of trifluoroacetic acid (10 ml) and anisole (0.5 g) for 15 minutes and then concentrated in vacuo. The residue is dissolved in ethyl acetate and treated with 5% NaHCO3. The aqueous phase is adjusted to pH 2 and the precipitated product is collected and dried.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:44])[C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C@H:25]([CH2:45][C:46]2[CH:51]=[CH:50][C:49](O)=[C:48]([O:53][CH3:54])[CH:47]=2)[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:33]=1)[C:29]([N:26]1[CH2:27][CH2:28][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][C@H:25]1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:48]([O:53][CH3:54])[CH:47]=1)=[O:44]
Reactant: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethane sulfonic acid anhydride (5.25 ml) was added dropwise over 30 minutes to an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-hydroxy-3-methoxybenzyl)piperazine (14.3 g) and 4-(dimethylamino)pyridine (0.47 g) and 2,6-lutidine (3.6 ml) in dichloromethane (150 ml) below 10° C. After being stirred at the same temperature for 2 hours, the reaction mixture was poured into water. The pH of the whole mixture was adjusted to 7 with diluted hydrochloric acid and the organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of toluene and ethyl acetate (100:1–5:1) to give the objective trifluoromethanesulfonic acid 4-[[(2R)-1-[3,5-bis(trifluoro-methyl)benzoyl]-4-benzylpiperazin-2-yl]methyl]-2-methoxyphenyl ester as an oil.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11]C)=[O:10])=[CH:5][CH:4]=1.[OH-:13].[Na+].Cl>O>[CH3:2][N:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][C:4]1=[O:13]
Reactant: [OH-]
Reactant: COC(=O)c1cc[n+](C)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Cn1ccc(C(=O)O)cc1=O
Temperature: 55 °C
Reaction time: 4 h

Procedure:
A solution of N-methyl-4-methoxycarbonylpyridinium iodide (2.00 g, 7.16 mmol) in water (10 mL) at room temperature was treated sequentially with 14M sodium hydroxide (1.0 mL) and 1.8M K3Fe(CN)6 (1.5 mL), stirred for 4 hours, treated again with 1.8M K3Fe(CN)6 once per hour for 4 hours, heated at 55° C. for one hour, cooled to room temperature, and treated with 6M HCl to pH 3. The precipitate was collected, washed with ether and dried under vacuum to provide 1.00 g of the desired product.
Reaction SMILES: [I:1][CH3:2].[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]([NH2:19])=[S:18])[CH:7]=[CH:8][C:9]=1[N:10]1[C:14]([CH3:15])=[N:13][CH:12]=[N:11]1>C(O)C>[IH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]([S:18][CH3:2])=[NH:19])[CH:7]=[CH:8][C:9]=1[N:10]1[C:14]([CH3:15])=[N:13][CH:12]=[N:11]1
Reactant: CI
Reactant: Cc1ncnn1-c1ccc(NC(N)=S)cc1F
Solvent: CCO
Product: CSC(=N)Nc1ccc(-n2ncnc2C)c(F)c1
Product: I
Temperature: 70 °C
Yield: 95.8 %

Procedure:
Step C (5) [79643-051]: Iodomethane (0.835 mL, 13.4 mmol) was added to a solution of 1-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (3.21 g, 12.8 mmol) in absolute ethanol (100 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed under high vacuum to afford methyl 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (4.82 g, 96% yield) as a white solid. LC-MS (M+H)+ 266.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12 (s, 1 H), 7.77 (t, J=8.5 Hz, 1 H), 7.64 (dd, J=11.0, 2.1 Hz, 1 H), 7.37 (dd, J=8.4, 1.4 Hz, 1 H), 2.72 (s, 3 H), 2.36 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11]O.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[ClH:1].[Cl:19][CH2:11][C:7]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:15]=[C:14]([Cl:16])[CH:13]=2)[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccn1Cc1cc(Cl)cc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 188.5 %

Procedure:
[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-yl]-methanol (1.7 g, 6.63 mmol) was dissolved in chloroform (16 mL) and diluted with thionyl chloride (2.9 mL, 40 mmol). The reaction was warmed to reflux. After 4 h, the reaction was concentrated to yield 1.95 g of 2-chloromethyl-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride as a pale yellow solid (95%).
Reaction SMILES: CO[C:3](=[O:26])[C:4]([CH:6]1[N:17]2[C:18]3[C:14]([CH:15]=[CH:16]2)=[CH:13][CH:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:10]=3[CH2:9][N:8]=[CH:7]1)=O.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:33][NH:34]2)=[CH:30][CH:29]=1>>[C:22]([O:21][C:19]([CH:12]1[CH2:11][C:10]2[CH2:9][N:8]=[CH:7][CH:6]([C:4]3[C:3](=[O:26])[NH:40][C:38](=[O:39])[C:37]=3[C:32]3[C:31]4[C:35](=[CH:36][C:28]([F:27])=[CH:29][CH:30]=4)[NH:34][CH:33]=3)[N:17]3[C:18]=2[C:14]([CH:15]=[CH:16]3)=[CH:13]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)C1C=NCC2=c3c(ccn31)=CC(C(=O)OC(C)(C)C)C2
Product: CC(C)(C)OC(=O)C1C=c2ccn3c2=C(CN=CC3C2=C(c3c[nH]c4cc(F)ccc34)C(=O)NC2=O)C1

Procedure:
Beginning with (6-(tert-butoxycarbonyl)-4,5-dihydro-6H-[1,4]diazepino[6,7,1-hi]indol-1-yl)oxoacetic acid methyl ester and 6-fluoroindole-3-acetamide, the title compound was prepared essentially as described in EXAMPLE 133.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
1.57 g (10 mmol) of bromobenzene and 4.15 g (30 mmol) of K2CO3 are added to a solution of 1.83 g (15 mmol) of phenylboronic acid in 20 ml of tetrahydrofuran. After the mixture has been stirred at room temperature for 15 minutes, 0.21 g (0.15 mmol) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is added, and the reaction mixture is heated under reflux for 3 hours. After cooling and addition of 100 ml of water, the reaction mixture is extracted with 200 ml of hexane. The organic phase is washed with water and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 0.99 g of biphenyl is isolated as a white solid. The yield is 64%, based on the bromobenzene employed.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(CO)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(COS(C)(=O)=O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of 82 mg of 2-ethyl-4-hydroxymethylpyridine and 79 mg of triethylamine in dichloromethane (2 mL) was added 82 mg of methanesulfonyl chloride, followed by stirring at room temperature for 1 hour. It was purified by PLC (chloroform:methanol=10:1), dissolved in ethyl acetate, washed with an aqueous sodium bicarbonate solution and then with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 47 mg (yield 36%) of a title compound as a yellow oily substance.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COCCN
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COCCNc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)c1
Yield: 34 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 2-methoxyethylamine instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate=50:50 to 0:100, 78 mg, 34%) which was obtained as an off-white foam. MS: m/e=407.4 [M+H]+.
Reaction SMILES: C[C@@:2]1(O[C@H:10]([CH2:12]Br)[C@@:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:9])[C@:6]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:7])[C@:4]1([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:5])[OH:3]>C(O)(C)C.O.[Zn]>[C:32]1([CH2:31][O:30][C@@:4]([C@:6]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C@@:8]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH:10]=[CH2:12])[OH:9])[OH:7])([OH:5])[CH:2]=[O:3])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@]1(O)O[C@H](CBr)[C@](O)(OCc2ccccc2)[C@@](O)(OCc2ccccc2)[C@@]1(O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(C)O
Solvent: O
Product: C=C[C@](O)(OCc1ccccc1)[C@@](O)(OCc1ccccc1)[C@](O)(C=O)OCc1ccccc1

Procedure:
Mix methyl-2,3,4-tris(phenylmethoxy)-6-bromo-6-desoxy-α-D-mannopyranose (20.968 g, 39.75 mmol) and activated zinc dust (20.50 g, 314 mmol) in isopropanol (300 mL) and water (55 mL). Heat at reflux for 38 minutes, cool and filter. Rinse the zinc dust with a mixture of ethyl acetate/water, filter and dilute the filtrate with water. Extract with a mixture of ethyl acetate/cyclohexane (3×) and wash the combined organic extracts with water. Evaporate the solvent in vacuo to give 2,3,4-tris(phenylmethoxy)-5,6-dideoxy-D-lyxo-hex-5-enose.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:10]([O:23][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C(OCC1CO1)C1CO1
Reactant: CCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of tridecanol.