Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]#[C:27][C:28]([O:31][CH3:32])([CH3:30])[CH3:29])[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:32][O:31][C:28]([CH3:30])([CH3:29])[C:27]#[C:26][C:17]1[CH:18]=[C:19]2[C@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:9]3[C:10](=[CH:11][CH:12]=[C:7]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)[CH:8]=3)[O:13][C:14]2=[N:15][CH:16]=1
Reactant: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 70 °C

Procedure:
A vial was charged with (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (104 mg, 0.210 mmol), pyridin-3-ylboronic acid (77 mg, 0.629 mmol), and tetrakis(triphenylphosphine)palladium (24.22 mg, 0.021 mmol). The vial was purged with Ar (g), then DMF (1048 μL) and potassium carbonate (524 μL, 1.048 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was capped and heated in a Biotage Initiator microwave reactor for 1.5 h at 70° C. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3-methoxy-3-methylbut-1-ynyl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27](O)[C:28](=[CH:30][CH:31]=1)[OH:29].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:24][C:25]1[CH:26]=[CH:27][C:28]2[O:29][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)([C:15]3[CH:16]=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=3)[O:23][C:30]=2[CH:31]=1
Reactant: CSc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Oc1ccc(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CSc1ccc(C2(C3CCNCC3)Oc3ccc(F)cc3O2)cc1
Yield: 33.6 %

Procedure:
A solution of 4-(4-methylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 28) (168 mg, 0.50 mmol), 4-fluorocatechol (128 mg, 2.0 mmol) and p-TsOH.H2O (190 mg, 1.0 mmol) in xylene (50 mL) was heated at reflux under a Dean-Stark trap for 41 hours. Standard work-up and purification gave 4-[5-fluoro-2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (58 mg, 34%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:1][CH2:4][CH2:11][CH2:10][CH3:9])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: CCCCN=Cc1cccc([N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 194.9 %

Procedure:
To a solution of 64 g (0.42 mole) 3-nitrobenzaldehyde in benzene was added 29.2 g of D-butylamine. The mixture was heated to reflux in a flask equipped with a Dean-Stark trap. After 90 minutes, the theoretical amount of water had separated, and the mixture was cooled and the solvent removed under vacuum, to give 84.4 g of N-(3-nitrobenzylidene)-1-butanamine.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CCO>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=[N:26][OH:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.3 %

Procedure:
To a solution of 3-((2-(4-benzylpiperidin-1-yl)ethyl)oxy)benzaldehyde (200 mg, 0.620 mmol) in 6 mL of 50% aqueous EtOH was added a solution of hydroxylamine hydrochloride (110 mg, 1.55 mmol) and sodium acetate (246 mg, 2.77 mmol) in 50% aqueous EtOH (10 mL). The resulting solution was allowed to stir at room temperature for 3 days. The EtOH was evaporated and a colorless solid was collected by filtration and dried to give the product (160 mg, 70%): mp 141-143° C.; 1H NMR (CDCl3) 1.40 (m, 2 H), 1.50 (m, 1 H), 1.64 (m, 2 H), 2.12 (m, 2 H), 2.54 (m, 2 H), 2.85 (s, 2 H), 3.08 (m, 2 H), 4.21 (m, 2 H), 6.88-7.28 (m, 9 H), 8.04 (s, 1 H), 10.00 (bs, 1 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH2:15][OH:16])=[CH:11][C:12](O)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10](=[CH:11][CH2:12][OH:13])[CH2:15][OH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(=CC(=O)O)CO
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=CCO)CO
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A 2.210 g (9.69 mmol) sample of 3-((t-butyldimethylsilyloxy)methyl)-4-hydroxybut-2-eneoic acid, 1,4-lactone, from Example 336A, was dissolved in 6 mL of methylene chloride, cooled in a dry ice bath, and 14.2 mL (21.3 mmol) of DIBAL was added. The mixture was stirred at -78° C. for 4 hours, allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to -78° C. and quenched with 1.53 mL of methanol and 2.55 mL of water. The mixture was filtered, and the filtrate concentrated and chromatographed on silica gel, eluting with 50% and 90% ethyl acetate in hexane. The solvent was removed and the product dried to afford 1.055 g of the title product, which was taken directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][CH2:11][CH3:12])=[C:4]([C:14]#[N:15])[N:3]=1.[OH-].[Na+].C(O)(=[O:20])C>CO.O>[CH2:10]([C:9]1[NH:15][C:14](=[O:20])[C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH2:11][CH3:12]
Reactant: CC(=O)O
Reactant: CCCC(=O)Nc1ccc(Cl)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1nc2ccc(Cl)nc2c(=O)[nH]1

Procedure:
To a solution of 0.56 g (2.5 mol) of 2-chloro-5-(N-butyroyl)amino-6-cyano-pyridine in 5 ml of MeOH was added 2.78 ml (5.56 mmol) of 2N NaOH followed by 0.33 ml (5.0 mmol) of 30% H2O. The reaction mixture was diluted with 10 ml of water and acidified with acetic acid. The mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine and dried over MgSO4. The solution was filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from MeOH to give 0.35 g of pale yellow needles. mp: 264°-266° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:47]/[O:48][CH3:49])/[C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:42]([OH:44])=[O:43])=[C:15]([CH2:18][NH:19][C:20]4[N:21](C)[N:22]=[C:23](OC(C5C=CC=CC=5)C5C=CC=CC=5)[C:24](=[O:26])[N:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:50]1([O:56]C)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:47]/[O:48][CH3:49])/[C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:42]([OH:44])=[O:43])=[C:15]([CH2:18][NH:19][C:20]4[NH:21][N:22]=[C:23]([CH2:50][OH:56])[C:24](=[O:26])[N:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)CS[C@H]12)c1csc(N)n1
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3nc(=O)c(CO)n[nH]3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 25 %

Procedure:
A solution of 7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]-3-[(2,5-dihydro-6-diphenylmethoxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)aminomethyl]ceph-3-em-4-carboxylic acid (400 mg.) in anisole/TFA (1:1 v/v; 10 ml.) was allowed to stand at ambient temperature for 20 minutes. The solvent was evaporated and the residue was dissolved in an aqueous ammonium carbonate buffer, pH6, and purified by HPLC using ammonium carbonate buffer/MeOH 92:8 v/v as eluant to give 7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]-3-[(2,5-dihydro-6-hydroxymethyl-5-oxo-1,2,4-triazin-3-yl)aminomethyl]ceph-3-em-4-carboxylic acid (yield 25%) having the following nmr in solvent B:--3.52(s,3 H); 3.6(s, 2 H); 4.04(s, 3 H); 4.4(s, 2 H); 5.18(d,1 H); 5.84(d, 1 H); 7.1(s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](OB(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(N(CC)CC)C>C(OCC)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]([O:26][CH3:25])=[O:28])[CH2:20]3)=[O:18])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1cccc(N2CCCC(C(=O)NCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.1 %

Procedure:
N-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyl]piperidine-3-carboxamide hydrochloride (123 mg, 0.318 mmol) was suspended in diethyl ether. The suspension washed sequentially with a 0.1 mol/L aqueous sodium hydroxide solution and brine and was dried over magnesium sulfate. The solvent was then evaporated and the resulting residue was dissolved in dichloromethane (10 mL). To this solution, 3-(methoxycarbonyl)phenylboric acid (114 mg, 0.636 mmol), molecular sieves 4 Å (300 mg), copper (II) acetate (122 mg, 0.636 mmol) and triethylamine (0.222 mL, 1.59 mmol) were added and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was filtered through Celite and a saturated aqueous sodium bicarbonate solution was added to the filtrate. The mixture was extracted with ethyl acetate. The extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=2:1->0:1) gave 20.1 mg (13%) of the desired compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][C:15](O)=[O:16])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[Cl:27][C:15](=[O:16])[CH2:14][CH:13]([C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12][CH:11]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(CC(=O)O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CC(CC(=O)Cl)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[2-(4-chlorophenyl)-1,3-thiazol-5-yl]-5-ethoxy-5-oxopentanoic acid (9.68 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. Oxalyl Chloride (2.0M in CH2Cl2; 25 mL) was added slowly. One drop of DMF was added to the reaction mixture. The reaction was warmed to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo to give the crude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC([O-])(C)C.[Na+]>O1CCOCC1>[C:2]1([NH:21][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
Following general procedure F, a mixture of chlorobenzene (102 μL, 1.0 mmol), N1-phenylbenzene-1,4-diamine (221 mg, 1.2 mmol), NaOt-Bu (192 mg, 2.0 mmol), 10 (8 mg, 1 mol %), 1 (5 mg, 1 mol %), and dioxane (1 mL) was heated to 80° C. for 2 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap; 0-50% EtOAc/Hexane) to provide the title compound as a off-white solid (260 mg, 99%), mp 152-154° C. 1H NMR (300 MHz, CDCl3) δ: 7.27 (t, J=7.5 Hz, 4H), 7.08 (s, 4H), 7.00 (d, J=8.0 Hz, 4H), 6.90 (t, J=7.5 Hz, 2H), 5.59 (s, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ: 144.7, 137.4, 129.6, 121.2, 120.2, 116.5 ppm. IR (neat, cm−1): 3389, 1601, 1512, 1496, 1382, 1313, 1271, 820, 742, 695. Anal. Calcd. for C18H16N2: C, 83.04; H, 6.19. Found: C, 82.81; H, 6.22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Br[C:16]1[N:17]=[C:18]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[S:19][CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[N:9]([C:16]1[N:17]=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[S:19][CH:20]=1)[CH:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Reactant: CS(=O)(=O)c1cc(F)c2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(S(C)(=O)=O)cc(F)c43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using 7-Fluoro-5-(methylsulfonyl)-1H-indole (intermediate 22) and tert-butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46).
Reaction SMILES: ClN1C(=O)CCC1=O.CSC.[C:12]([Si:16]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:17][C@H:18]1[CH2:23][C@@H:22]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]/[C:20](=[CH:42]/CO)/[C:19]1=[CH2:45])([CH3:15])([CH3:14])[CH3:13].[CH2:58]([Cl:60])Cl>>[Cl:60][CH2:58]/[CH:42]=[C:20]1\[C:19](=[CH2:45])[C@@H:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:23][C@@H:22]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21]\1
Reactant: ClCCl
Reactant: C=C1/C(=C\CO)C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: CSC
Product: C=C1/C(=C\CCl)C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.31 g (9.81 mmol) of N-chloro-succinimide in 34 ml of abs. CH2Cl2 was treated at -10° with 749 μl (10.2 mmol) of dimethyl sulfide. 15 Minutes later, 2.95 g (4.559 mmol) of (Z)-(3S,5S)-2-[3,5-bis-(tert-butyl-diphenyl-silanyloxy)-2-methylene-cyclohexylidene]-ethanol, dissolved in 10 ml of CH2Cl2, was slowly added to the resultant white suspension at the same temperature and then stirred for additional 30 minutes at RT. The reaction mixture was then poured onto crushed ice, extracted with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=97.5/2.5) yielded 2.76 g of (Z)-(3S,5S)-1-(2-chloro-ethylidene)-3,5-bis-(tert-butyl-diphenyl-silanyloxy)-2-methylene-cyclohexane as yellowish foam.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[C:23]2[C:30]([CH3:31])=[C:29]([C:32](=[O:34])[NH2:33])[S:28][C:24]=2[N:25]=[CH:26][N:27]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[C:23]2[C:30]([CH3:31])=[C:29]([C:32]([NH2:33])=[O:34])[S:28][C:24]=2[N:25]=[CH:26][N:27]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC3NC(=O)OC(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3N)c12

Procedure:
A reaction mixture of 2.1 g 1S,2S) {2-(2-(6-carbamoyl-5-methyl-thieno[2,3-d]pyrimidin-4-ylamino)-5-fluoro-phenoxy]-cyclopentyl}-carbamic acid tert-butyl ester, and 1.24 ml trifluoroacetic acid in 50 ml DCM was stirred for 3 days at 46° C. The mixture was concentrated, diluted with toluenel and concentrated. The residue was extracted with DCM and water, whereby the water layer had the pH range of 10. The organic layer was dried and concentrated in vacuo. The residue was purified by chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24]Br)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][S:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CSCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl mercaptan.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[S:18]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](Cl)=[O:25])(=[O:20])=[O:19])[CH:11]=[CH:10][CH:9]=1>>[CH:1]1([NH:7][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][S:18]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[N:8]=[CH:9][CH:10]=[CH:11]3)(=[O:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)c1cccc2cccnc12
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1ccccc1NS(=O)(=O)c1cccc2cccnc12
Yield: 57.4 %

Procedure:
50 mg of cyclohexylamine were reacted with 87 mg of 2-(quinoline-8-sulfonylamino)-benzoyl chloride in analogy to example 1 which resulted in 59 mg of an amorphous white solid. MS (ES): 410 (M+H)+
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[N:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3C=CC(C(N4CCN(C/C=C/C5C=CC=CC=5)CC4)=O)=CC=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@H:36]3[C@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([CH2:38][C:34]3[CH:35]=[CH:36][C:31]([C:30]([N:4]4[CH2:5][CH2:6][N:1]([C:7]5[CH:12]=[N:11][CH:10]=[CH:9][N:8]=5)[CH2:2][CH2:3]4)=[O:37])=[CH:32][CH:33]=3)[N:28]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: c1cnc(N2CCNCC2)cn1
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)N4CCN(c5cnccn5)CC4)cc3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A11 and 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl as described for compound 8. M.p. 124–126° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=1>CN(C=O)C>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[N:26][CH:25]=1)[CH3:28]
Reactant: CCc1cnc(Cl)nc1
Reactant: NCCc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cnc(NCCc2ccc(O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
Tyramine (5.52 g, 0.040 mol) in 40 ml of anhydrous DMF was treated with diisopropylethylamine (6.1 ml, 0.035 mol). After stirring at rt for 15 minutes, 2-chloro-5-ethylpyrimidine (4.25 ml, 0.035 mol) was added and the mixture heated at 80° C. for 14 hours. The solution was allowed to cool to room temperature and was partitioned between equal volumes of water and ethyl acetate. The aqueous phase was washed with ethyl acetate and the combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate-hexane to afford the title compound as a colorless solid (4.94 g; 58% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[C:12]([N+:20]([O-])=O)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[C:12]([NH2:20])=[CH:11][C:10]=1[C:23]([F:26])([F:24])[F:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(NCc2ccccc2)cc1-n1ccnc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(NCc2ccccc2)cc1-n1ccnc1
Yield: 96.2 %

Procedure:
A solution of N-benzyl-5-(1H-imidazol-1-yl)-4-nitro-2-(trifluoromethyl)aniline (190 mg; 0.52 mmol; 1 eq) and tin chloride dihydrate (591 mg; 2.62 mmol; 5 eq) in ethanol (2 ml) is stirred under argon at 80° C. for 4 h. Concentration, partition (ethyl acetate/aqueous sodium hydrogenocarbonate), addition of solid sodium hydrogenocarbonate to adjust the pH around 8, filtration over Celite, extraction of the cake solid with ethyl acetate, reunion of the organic phases, additional washings (aqueous ammonium chloride, brine), drying (magnesium sulfate) and concentration affords the title product (165 mg; 0.50 mmol; 96%) as a yellow solid.
Reaction SMILES: [F:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[F:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][OH:4]
Reactant: CCCCCC[C@@H](F)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@@H](F)CO
Reaction time: 16 h

Procedure:
--Ethyl (R)-(+)-2-fluorooctanoate 69 (20.0 g, 105 mol) in dry THF (30 ml) was added dropwise with stirring to a suspension of lithium aluminium hydride (6 g, 0.158 mol) under nitrogen and with water bath cooling. After the final addition the water bath was removed and the mixture was stirred for 16 h. Aqueous THF (50 ml, 1:3) was added dropwise with iced water-bath cooling followed by 20% hydrochloric acid until a clear solution was effected. The mixture was extracted with ether (3 times) and the combined organic solutions were washed with sat. sodium bicarbonate solution (twice) and brine, dried (MgSO4) and evaporated. The yellow oil was distilled to give (R)-(+)-2-fluorooctanol 70 which solidified on cooling (12.9 g, 83%), b.p. 110° C. at 20 mm Hg, [α]D18 =+6.2° (c 4.6 in CHCl3); νmax /cm-1 (film) 3600-3100br (OH), 2920, 2860, 1460, 1375, 1125sh, 1055br and 840; δ 0.90 (3H, t, Me), 1.14-1.80 (10H, m), 2.19 (1H, br s, OH), 3.69 (2H, br d, 3JHF 27, CH2OH), and 4.56 (1H, br d, 2JHF 51, CHF); m/z 149 (M+ 1), 137, 125, 115, 111, 97, 81 and 69.