Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:18][CH2:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:7])(C)(C)C>C(O)=O>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][CH2:19][O:18][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH:8]([C:6]([OH:7])=[O:5])[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Solvent: O=CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc2c(c1)OCC(C(=O)O)C2
Temperature: 60 °C
Yield: 83.8 %

Procedure:
tert-butyl-7-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]chromane-3-carboxylate (5.2 g, 11.95 mmol) was dissolved in 25 ml of formic acid and heated at 60° C. for 12 hrs. Formic acid was removed in vacuum pump and ether (25 ml) was added and heated for 10 minutes. The resultant suspension was cooled at −20° C. for 1 hr and filtered. The solid product was washed with 20 ml of diethyl ether and dried to give the compound 7-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]chromane-3-carboxylic acid as white powder (3.8 g, 84%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19][CH2:18]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:16])[CH2:24][CH2:23]2)[CH2:18][CH2:19]1
Reactant: O=C1COc2ccc(F)cc2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COc2ccc(F)cc2N1CCCN1CCC(OCC2CC2)CC1
Reaction time: 20 h
Yield: 57.2 %

Procedure:
A 4 mL vial was charged with 4-(3-chloropropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one (0.097 g, 0.4 mmol), 4-cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), NaI (0.075 g, 0.5 mmol), and K2CO3 (0.069 g, 0.5 mmol) in MeCN (1 mL) and shaken at 500 for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiO2; EtOAc) to give the title compound (0.056 g, 57%). 1H NMR (CDCl3) δ 6.80-6.71 (m, 2H), 6.52-6.47 (m, 1H), 4.38 (s, 2H), 3.77 (t, J=7.2 Hz, 2H), 3.17-3.13 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.59-2.56 (m, 2H), 2.19 (t, J=6.8 Hz, 2H), 1.95-1.89 (m, 2H), 1.75-1.62 (m, 4H), 1.50-1.41 (m, 2H), 0.89-0.86 (m, 1H), 0.38-0.33 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) δ 164.1, 158.3, 141.2, 129.8, 117.4, 109.4, 102.9, 74.7, 72.5, 67.6, 55.1, 51.4, 39.8, 31.3, 24.6, 10.9, 3.0.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH:49]1([C:53]([OH:55])=O)[CH2:52][CH2:51][CH2:50]1>>[CH:49]1([C:53]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:44][CH2:45]2)=[O:55])[CH2:50][CH2:51][CH2:52]1
Reactant: O=C(O)C1CCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C4CCC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (3.1 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using cyclobutanecarboxylic acid as the acylating agent. LCMS: m/e 724.8 (M+H)+, 3.66 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 1H), 3.83-3.54 (m, 2H), 3.53-3.38 (m, 3H), 2.91 (d, J=2.1 Hz, 1H), 2.85-2.71 (m, 2H), 2.62 (d, J=10.1 Hz, 3H), 2.55-2.39 (m, 2H), 2.36-1.18 (m, 29H), 1.75 (s, 3H), 1.22 (s., 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [C:1]1([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1C.[N+](C1C=CC=CC=1)([O-])=O.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH2:24].Br>CCCCCC>[CH3:22][C:23]([NH:12][C:10]([NH:9][C:1]1[CH:2]=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1)=[O:11])([CH3:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C)c1ccccc1
Reactant: Cc1ccc(NC(N)=O)c(C)c1
Agent: Br
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)NC(C)(C)c2ccccc2)cc1
Reaction time: 5 h

Procedure:
12.4 parts of 2,4 -xylylurea was suspended in 50 parts of nitrobenzene, and 30 parts of α-methylstyrene was added. The mixture was stirred while introducing anhydrous hydrobromic acid portionwise. When the amount of the mixture increased by 10 parts, the introduction of the hydrobromic acid was stopped. The reaction was then performed at 40° C. for 5 hours. The resulting reaction mixture was allowed to stand overnight. Then, 30 parts of n-hexane was added, and the mixture was further allowed to stand overnight. The precipitated crystals were recrystallized from 60% methanol to afford 13.4 parts of N-(α,α-dimethylbenzyl)-N'-(p-tolyl)urea having a melting point of 203° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl>CC(C)=O>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Oc1cc(N)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Oc1cc(NC(=O)OCc2ccccc2)c(F)cc1Cl
Yield: 91.1 %

Procedure:
2-Fluoro-4-chloro-5-methoxycarbonyloxyaniline (2.00 g, 6.86 mmol), potassium carbonate (1.42 g, 10.3 mmol), benzyl chloroformate (1.17 g, 6.86 mmol) and acetone (20 ml) as a solvent were charged into a 100 cc two-necked flask, and heated for 2 hours while refluxing. After completion of the reaction, the mixture was added to 1H hydrochloric acid (50 ml), and extracted with ethyl acetate (50 ml×3). After drying, the organic layer was concentrated to obtain substantially pure benzyl N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)carbamate as a solid (2.21 g, 91.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13]OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1c[nH]cn1
Reactant: C=CCC(COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: C=CCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Yield: 70.3 %

Procedure:
4-(3,4-Dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (5.4 g) (see Preparation 23) and imidazole (3.6 g) were dissolved in anhydrous acetonitrile (40 ml) and the mixture heated under reflux for 100 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and washed with sufficient aqueous sodium carbonate solution to ensure that the aqueous phase reached pH14. The two phases were separated and the aqueous phase extracted with dichloromethane (100 ml). The organic phases were combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 100:0 changing to 98:2, by volume, dichloromethane:methanol, to give 4-(3,4-dichlorophenyl)-5-(imidazol-1-yl)pent-1-ene (3.45 g) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)c(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
A mixture of (5-methyl-2-nitrophenyl)phenylamine (1.5 g, 6.57 mmol) and 10% Pd/C (750 mg) in EtOAc (25 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 5 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo affording 4-Methyl-N2-phenylbenzene-1,2-diamine as a brown solid (1.29 g, 99%). LCMS: RT 2.61 min [M+H]+ 199.2.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:66]1[CH:71]=[CH:70][N:69]([CH2:72][CH2:73][CH2:74][CH3:75])[C:68](=[O:76])[CH:67]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:72]([N:69]1[CH:70]=[CH:71][C:66]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:67][C:68]1=[O:76])[CH2:73][CH2:74][CH3:75]
Reactant: CCCCn1ccc(Br)cc1=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCn1ccc(N2CCC(c3ccccc3)CC2)cc1=O
Temperature: 100 °C

Procedure:
4-Phenylpiperidine (0.45 g, 2.78 mmol), palladium(II) acetate (0.016 g, 0.069 mmol), sodium tert-butoxide (0.34 g, 3.5 mmol) and BINAP (0.065 g, 0.104 mmol) were added to a solution of intermediate D6 (0.32 g, 1.39 mmol) in toluene (5 ml). The reaction mixture was heated at 100° C. for 16 hours in a sealed tube, after which it was cooled to room temperature and then diluted with water (5 ml) and extracted with EtOAc (3×5 ml). The combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 0-4% methanol/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D19 (0.38 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.NC1C=CC(S(C(=C)C#N)(=O)=O)=CC=1.S(=O)(=O)(O)O.C(N(CC)CC)C.[C:42]1([CH3:52])[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>CN(C)C=O.O>[CH3:52][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)C=CS(=O)(=O)c1ccc(N)cc1
Agent: C=C(C#N)S(=O)(=O)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC(N)=O)cc2)cc1
Reaction time: 16 h

Procedure:
22.6 g (0.1 mol) of 3-(4-aminobenzenesulfonyl)acrylamide, prepared by hydrolysis of 3-(4-aminobenzenesulfonyl acrylonitrile with a 1:1 molar mixture of concentrated sulfuric acid and water, is dissolved in dimethylformamide (100 ml), and 14.5 ml triethylamine (0.1 mol) are added thereto. A solution of p-toluenesulfonyl chloride (19.1 g, 0.1 mol) in 50 ml dimethylformamide is added dropwise at room temperature, and the reaction mixture is left undisturbed for 16 hours. The product is recovered by precipitation with water and recrystallization from ethanol. There is thus produced 3-[4-(4-methylbenzenesulfonamido)benzenesulfonyl]acrylamide: ##SPC14##
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[O:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC2C=CC(OC)=CC=2OC)[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[O:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnnc3N)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nnccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 74.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(3-aminopyridazin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (45 mg, 0.073 mmol) prepared in Example 82f, triethylsilane (0.06 mL), trifluoroacetic acid (0.08 mL) and dichloromethane (0.76 mL), to yield the title compound (25 mg, 74%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]2)=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2cc(C)c(N)c([N+](=O)[O-])c2)CC1

Procedure:
A mixture of 4-bromo-2-methyl-6-nitro-phenylamine (5 g, 21.64 mmol), 1-acetylpiperazine (4.2 g, 32.46 mmol), palladium acetate (244 mg, 1.08 mmol), tri-tert-butylphosphine (440 mg, 2.16 mmol) and sodium tert-butoxide (4.2 g, 43.29 mmol) in toluene (70 mL) was heated to
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[CH2:25][CH:24]2[CH:22]([CH2:23]2)[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[OH:18][CH2:19][CH:20]1[CH2:25][CH:24]2[CH:22]([CH2:23]2)[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CC(C)(C)OC(=O)N1C2CC2C[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CO)CC2CC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a solution of (3R)-tert-butyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (D31) (2.1 g, 4.6 mmol) in THF (130 ml), TBAF 1M sol in THF (9.2 ml) was added and the solution was stirred at RT for 18 hours. Solvent was evaporated and the residue purified by Biotage SNAP-Si column (50 g), eluting with DCM/Et2O from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D32) (490 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3Br)[CH2:15]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)#[CH:32]>CN(C)C=O.[Pd].C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:32]#[C:31][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:15]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)N2Cc3cccc(Br)c3C2)cc1OC
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2Cc3cccc(C#Cc4ccccn4)c3C2)cc1OC
Temperature: 90 °C
Reaction time: 72 h
Yield: 12.5 %

Procedure:
2-(3,4-Dimethoxybenzenesulphonyl)-4-bromoisoindoline (0.19 g), triethylamine (0.10 ml), 2-ethynylpyridine(0.06 g) and bis (triphenylphosphine)palladium(II)chloride (10%) in anhydrous N,N-dimethylformamide(2 ml) were stirred together under an inert atmosphere and heated to 90° C. After 20 hours further 2-ethynylpyridine(0.12 g) and palladium catalyst (20%) were added and heating continued for 3 days. The reaction mixture at room temperature was diluted with ethyl acetate, filtered through a pad of silica and the filtrate evaporated in vacuo to yield a yellow residue. Purification by column chromatography, eluting with a 20-100% ethyl acetate in hexane gradient afforded the title compound (25 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:34])=O)(C)(C)C.[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([CH3:43])[C:37]=1[CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:37]3[C:38]([CH3:43])=[CH:39][CH:40]=[C:41]([F:42])[C:36]=3[F:35])[C:11]2=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1c(C)ccc(F)c1F)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 14.2 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 5.94 mmol) was reacted with 1-(2,3-difluoro-6-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (18 mmol) in toluene to give the title compound as a white solid (510 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH:6]([OH:8])[CH3:7].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:8][CH:6]([CH3:7])[CH:5]([O:9][CH3:10])[O:4][CH3:3])[N:15]=[CH:14][N:13]=1
Reactant: COC(OC)C(C)O
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(OC)C(C)Oc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.13 g of sodium hydride (60% in oil), to which 5.4 ml of a 0.5 mol/l solution containing 1,1-dimethoxy-2-propanol in tetrahydrofuran was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.4 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at 0° C. for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of 4-chloro-6-(2,2-dimethoxy-1-methylethoxy)pyrimidine.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([OH:15])[CH2:12][CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO>[Si:1]([O:8][C@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][CH2:11][C@@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
(1S,2S,4S)-4-(Benzyloxy)-2-(tert-butyldimethylsilyloxy)-N-((S)-1-phenylethyl)cyclohexanamine MS: 440 (M+H)+; HPLC Ret Time: 2.83 min (YMC Xterra S5 4.6×50 mm column, 3 min gradient, 4 mL/min) was obtained from (1S,2S,5S)-5-(benzyloxy)-2-((S)-1-phenylethylamino)-cyclohexanol) 39A as described in 39B. It was then converted to the product as described in 39B and exhibited an [a]25589 19.2 (c 5.7, MeOH).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCc1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncccc2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
The suspension of 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (example 1a, 3.0 g, 10.5 mmol), thiophene methyl amine (2.4 g, 21.0 mmol) and diisopropylethylamine (DIEA) (3.66 mL, 21.0 mmol) in acetonitrile (30 mL) was stirred under at 80° C. for 12 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-10% methanol in methylene chloride in 30 min) afforded 2-[(thiophen-2-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (2.5 g, 67%) as a light yellow solid: LC-MS m/e 352 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1.ClC1N=C(OC2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1>>[Cl:8][C:4]1[N:3]=[C:2]([O:16][C@@H:15]2[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][C@H:10]2[F:9])[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Reactant: Clc1cncc(Cl)n1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cncc(Cl)n2)[C@H](F)C1

Procedure:
tert-butyl trans-4-[(6-chloropyrazin-2-yl)oxy]-3-fluoropiperidine-1-carboxylate was prepared from 2,6-dichloropyrazine and tert-butyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate using the conditions described for the preparation of tert-butyl 4-[(6-chloropyrazin-2-yl)oxy]piperidine-1-carboxylate (Compound 1, Step 3). LRMS (ESI) calculated for C14H19ClFN3O3[M+Na]+, 354.1; found 354.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18](=[O:30])[NH:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=2)[CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:10]([O:17][C:18]([NH:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](/[CH:33]=[CH:32]/[C:31]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=2)[CH2:21]1)=[O:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(NC1Cc2ccc(Br)cc2C1)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc2c(c1)CC(NC(=O)OCc1ccccc1)C2
Temperature: 180 °C
Yield: 114.9 %

Procedure:
A mixture of palladium(II) acetate (3 mg, 0.01 mmol), Tri-o-tolylphosphine (7 mg, 0.02 mmol) and DIPEA (0.088 mL, 0.5 mmol) was stirred in MeCN (2 mL) at 60° C. under a nitrogen atmosphere for 20 minutes in a 5 mL microwave vial. Benzyl(5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate (174 mg, 0.5 mmol) and ethyl acrylate (28 μL, 0.25 mmol) were added and the mixture was heated in the microwave at 180° C. for 0.5 h. The mixture was adsorbed onto silica and purified by chromatography with 0-40% EtOAc/isohexane as eluent to give the title compound (105 mg, 57%) as a gum; 1H NMR (CDCl3) δ 1.32 (t, 3H), 2.62-2.88 (m, 2H), 3.12-3.36 (m, 2H), 4.18-4.29 (m, 2H), 4.46-4.62 (m, 1H), 4.76 (d, 1H), 5.09 (s, 2H), 6.32-6.41 (m, 1H), 7.10-7.44 (m, 8H), 7.57-7.68 (m, 1H); MS m/e MH+ 366.