Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:8]([NH:24][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)/C=C\C(=O)O
Yield: 65.7 %

Procedure:
19.6 g of maleic acid anhydride are dissolved in 500 ml of toluene at 90° C. The temperature is maintained at 90° C. while 48.2 g of hexadecylamine, dissolved in 200 ml of toluene are added dropwise within 45 minutes. After one more hour at 90° C. followed by cooling, the resulting precipitate is suction filtered and washed with methanol. 44.5 g of N-hexadecylmaleic amide melting at 101° to 102.5° C. are obtained.
Reaction SMILES: Cl[O-].[Na+].[CH:4]1([CH:7]([O:11][CH2:12][CH:13]=[N:14][OH:15])[CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:5]1.C(N(CC)CC)C>ClCCl.O>[CH:4]1([C@@H:7]2[O:11][CH2:12][C:13]3=[N:14][O:15][CH2:10][C@@H:9]3[CH2:8]2)[CH2:6][CH2:5]1
Reactant: C=CCC(OCC=NO)C1CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C1O[C@@H](C2CC2)C[C@H]2CON=C12

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 27.1 mL, 22.4 mmol) was added drop-wise over 24 minutes to a solution of 2-[(1-cyclopropylbut-3-en-1-yl)oxy]-N-hydroxyethanimine (C17) (1.85 g, 10.9 mmol) and triethylamine (0.114 mL, 0.818 mmol) in dichloromethane (64 mL) that was immersed in a room temperature water bath. The rate of addition was adjusted to maintain the internal temperature of the reaction between 19.5° C. and 22.8° C. After completion of the addition, the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo (300 mbar, 40° C.) to provide the product as a pale yellow oil. The indicated relative stereochemistry of compound C18 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. Yield: 1.73 g, 10.3 mmol, 94%. GCMS m/z 167 [M+]. 1H NMR (400 MHz, CDCl3) δ 4.73 (d, J=13.5 Hz, 1H), 4.61 (dd, J=10.2, 8.0 Hz, 1H), 4.14 (dd, J=13.5, 1.0 Hz, 1H), 3.80 (dd, J=11.5, 8.0 Hz, 1H), 3.36-3.48 (m, 1H), 2.83 (ddd, J=11.0, 8.0, 1.8 Hz, 1H), 2.31 (ddd, J=13.0, 6.5, 1.5 Hz, 1H), 1.64 (ddd, J=12.8, 11.4, 11.3 Hz, 1H), 0.89-0.98 (m, 1H), 0.51-0.64 (m, 2H), 0.38-0.45 (m, 1H), 0.21-0.28 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[Na].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCOCC1>[CH2:10]([O:1][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC1(CO)COC1
Reactant: CCCCCCCCBr
Agent: [Na]
Solvent: C1COCCO1
Product: CCCCCCCCOCC1(C)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.9 %

Procedure:
Into a 5 liter, three-neck flask, fitted with a stirrer, reflux condenser, and nitrogen inlet tube, were placed 245 g (2.4 mole) of 3-hydroxymethyl-3-methyloxetane and 3000 ml of p-dioxane. To this solution 47 g (2 mole) of solid sodium metal was added, and the pot temperature was raised to reflux. Heat was maintained until all of the sodium had dissolved. 400 g (2 mole) of 1-bromooctane was added, and the reflux was resumed for 3 days. The mixture was cooled to room temperature, and the solid sodium bromide was filtered off using celite. The solvent was removed by evaporation and the product was distilled at 80° C. and 0.3-mm pressure. Redistillation from calcium hydride gave 231 g of polymerizable monomer, representing a 58 percent yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH:12][CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.[Br:26][C:27]1[C:28](Cl)=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1>C(Cl)Cl>[Br:26][C:27]1[C:28]([N:12]([CH2:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14][C:15]([NH:17][CH3:18])=[O:16])=[N:29][C:30]([Cl:33])=[N:31][CH:32]=1
Reactant: CNC(=O)CCNCc1cc(OC)cc(OC)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)CCN(Cc1cc(OC)cc(OC)c1)c1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
3-[(3,5-dimethoxyphenyl)methylamino]-N-methyl-propanamide (Intermediate 98; 1 g, 3.96 mmol) was dissolved in DCM (10 mL) and triethylamine (0.68 mL, 4.36 mmol). 5-bromo-2,4-dichloropyrimidine (Aldrich; 993 mg, 4.36 mmol) was added and the mixture stirred at room temperature for 18 hours. The mixture was diluted with DCM and washed with water, brine, dried (MgSO4), filtered and evaporated to give a yellow gum which was purified on a 40 g ISCO companion eluting with 50-70% ethyl acetate in iso-hexane to give the title compound as a white solid (461 mg, 26%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH2:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]>N1C=CC=CC=1.CN(C)C=O.CCCCCC.O>[C:2]1([CH:1]=[C:13]2[S:9][C:10](=[O:15])[NH:11][C:12]2=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1NC(=O)C(=Cc2ccccc2)S1
Temperature: 55 °C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
Benzaldehyde (0.78 mol, 82.8 g) and 2,4-thiazolidinedione (0.85 mol, 100 g) were heated to reflux in a mixture of pyridine (215 ml) and dimethylformamide (400 ml) for 18 hours. The reaction mixture was cooled to 55° C. and diluted with hexane (360 ml) and water (900 ml) and stirred for 1 hour after cooling to room temperature. The product was collected to afford 175 g of pale yellow solid; m.p. 246°-248° C.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)(=[O:25])[CH2:23][CH3:24]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, a saturated sodium chloride solution 50 ml, saturated sodium bicarbonate solution 50 ml, and a saturated salt solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 1 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 300.6 mg.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:47]=[O:48])=[C:7]([Cl:49])[N:6]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CCO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:47][OH:48])=[C:7]([Cl:49])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an EtOH (500 mL) solution of intermediate (11a) (41.0 g, 61.8 mmol) was added solid NaBH4 (2.8 g, 74.1 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to 0° C., the reaction was quenched by dropwise addition of a 50/50 solution of acetic acid/water until no effervescence was observed. EtOAc (500 mL) was added and the organic was washed three times with saturated aqueous NaCl (100 mL). Solvent was removed and purification was achieved by silica gel chromatography (50:50 EtOAc:hexanes) using an isocratic gradient to provide intermediate (11b) as a white solid (37 g). MS m/z: [M+H+] calcd for C41H37ClN6O, 665.28; found 665.3. 1H-NMR (d4-MeOH): 0.79 (m, 3H), 1.20 (m, 2H), 1.46 (m, 2H), 2.45 (m, 2H), 4.30 (s, 2H), 5.19 (s, 2H), 6.83-6.90 (m, 8H), 7.05 (d, 2H), 7.23-7.33 (m, 10H), 7.53 (m, 2H), 7.81 (d, 1H).
Reaction SMILES: C(O)C.C([O:6][C:7]([C:9]1[N:10]=[C:11]([N:14]2[CH:20]([CH3:21])[CH2:19][C:18]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:17]=3[C:16]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[N:15]2)[S:12][CH:13]=1)=[O:8])C.[OH-].[Na+].C(O)(=O)C>O>[C:7]([C:9]1[N:10]=[C:11]([N:14]2[CH:20]([CH3:21])[CH2:19][C:18]3[CH:22]=[C:23]4[O:28][CH2:27][O:26][C:24]4=[CH:25][C:17]=3[C:16]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[N:15]2)[S:12][CH:13]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1csc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nc(C(=O)O)cs1)OCO3
Temperature: 90 °C
Yield: 91.2 %

Procedure:
A mixture of 9 ml of ethanol, 0.85 g (1.89 mmol) of (±)-7-(4-ethoxycarbonyl-thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (Example 8) and 7 ml of 1N sodium hydroxide solution was stirred at 90° C. After cooling, it was acidified with acetic acid, diluted with water and the precipitated crystals were filtered off, washed with water and dried to yield 0.78 g (98%) of the title compound; Mp.: >260° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:23][C:24]([F:30])([F:29])[S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:15][S:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:16])[C:2]=1[O:1][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(O)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(OS(=O)(=O)C(F)(F)F)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
8.8 g (0.036 mol) of methyl 3-hydroxy-4-methanesulfonyl-2-methyl-benzoate was dissolved in 100 ml of methylene chloride, and 8.3 g (0.11 mol) of pyridine was added. After the solution was cooled to 0° C., 12.2 g (0.043 mol) of anhydrous trifluoromethanesulfonic acid was added. After stirring at room temperature for 1 hour, the reaction mixture was washed with 1N hydrochloric acid and subsequently with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 13.5 g of methyl 4-methanesulfonyl-2-methyl-3-(trifluoromethanesulfonyl)oxybenzoate. Yield=99%.
Reaction SMILES: Cl.[C:2]1([CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][NH2:26])[CH2:21][CH2:20]3)[CH:14]=2)[O:9]1.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CN(C)C=O.O>[C:28]([O:32][C:33](=[O:34])[NH:35][CH2:36][C:37](=[O:38])[NH:26][CH2:25][C@H:22]1[CH2:23][CH2:24][C@@H:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[O:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:27])[CH2:17][CH2:16]3)[CH2:20][CH2:21]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@@H](CN)CC3)ccc2O1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1C1CCc2cc(O[C@H]3CC[C@@H](CNC(=O)CNC(=O)OC(C)(C)C)CC3)ccc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 110 mg of [cis-4-(2-o-tolyl-chroman-6-yloxy)-cyclohexylmethyl]amine hydrochloride (0.28 mmol), 75 mg of N-tert-butoxycarbonylglycine (0.43 mmol), 76 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.40 mmol) and 54 mg of hydroxybenzotriazole (0.40 mmol) at room temperature in 2 ml of dimethylformamide 0.16 ml of N-methylmorpholine (1.42 mmol) were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with diluted aqueous sodium carbonate solution, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography using ethyl acetate/heptane/methanol 5:10:1 as eluent. 95 mg of the title compound were isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].C([C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)=C>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru-4](Cl)(Cl)=CC1C=C(S(N(C)C)(=O)=O)C=CC=1OC(C)C.ClCCl>[F:38][C:37]([F:39])([F:40])[C:35]1[CH:36]=[C:31](/[CH:17]=[CH:16]/[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[Br:1])[CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=1
Reactant: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru-4](Cl)(Cl)=Cc2cc(S(=O)(=O)N(C)C)ccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: O=C(N[C@H](CCC/C=C/c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccc1Br)OCc1ccccc1
Temperature: 60 °C
Yield: 90.9 %

Procedure:
To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (1.5 g, 3.29 mmol), 1-ethenyl-3,5-bis(trifluoromethyl)benzene (1.58 g, 6.57 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II)dichloride (41 mg, 0.57 mmol) was added before heating at 60° C. for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,5E)-6-[3,5-bis(trifluoromethyl)phenyl]-1-[2-bromo-5-(trifluoromethyl)phenyl]hex-5-en-1-yl}carbamate (2.0 g, 2.99 mmol). 1H NMR (500 MHz, CDCl3) δ7.81 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 5.82 (m, 1H), 5.05 (m, 2H), 4.41 (m, 1H), 3.82 (s, 1H), 2.13 (m, 2H), 1.76 (m, 1H), 1.42 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19](OCC)=[O:20])[CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:1][N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([CH2:19][OH:20])[CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1CC2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CN1CCC(=C2c3ccccc3CCc3ccc(CO)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A solution of 5.3 g of the ethyl ester from Step A in 200 ml of ether was added dropwise over about 30 minutes to a stirred mixture of 0.53 g of LiAlH4 and 50 ml of ether. After the addition was complete the mixture was stirred 1 hour at ambient temperature, warmed to reflux and allowed to cool spontaneously to ambient temperature. With vigorous stirring a saturated aqueous solution of ammonium chloride was added slowly until a granular precipitate and a clear ether phase formed. Anhydrous magnesium sulfate was added. After stirring a short time the mixture was filtered and the filtrate was concentrated to dryness to give 2.28 g of 1-methyl-4-(10,11-dihydro-3-hydroxymethyl-5H-dibenzo[a,d]-cyclohepten-5-ylidene)piperidine, m.p. 178°-181° C. after recrystallization from acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH3:26].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:25][CH3:26])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCBr
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of compound 35 (4 mmol, 948 mg) in 5 mL DMF, potassium carbonate (K2CO3, 8 mmol, 1.1 g) and bromoethane (4.8 mmol, 523 mg) were added. The reaction was stirred overnight at 60° C. Water (2 mL) was added to dissolve the unreacted potassium carbonate, and the reaction mixture was then extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried over Na2SO4. After removal of the solvent, the crude product was purified by using flash chromatography (0-30% ethyl acetate/hexane) to give the title product 36 (90% yield).
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:28]=3)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.C(Cl)Cl.FC(C(O)=O)(F)F>>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:31][CH:32]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCN4CCCCC4)cc3)ncc2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)c1ccc(-c2nc(Nc3ccc(CCN4CCCCC4)cc3)ncc2C#N)cc1
Yield: 77.5 %

Procedure:
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-piperidin-1-ylethyl)phenyl]pyrimidine-2-amine (380 mg) was stirred in 50% v/v CH2Cl2-TFA (5 mL) at room temperature for 30 min. The solvent was removed under reduced pressure and the resulting residue was redissolved in CH2Cl2, washed with saturated aqueous NaHCO3, dried (MgSO4) and evaporated to give the title compound (240 mg) as a yellow solid, m.p. 150°. δH (CDCl3) 8.70 (1H, s), 8.01 (2H, d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.22 (2H, d, J 8.0 Hz), 2.84 (2H, m), 2.63 (2H, m), 2.52 (4H, m) and 1.51 (6H, s).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.ClC(OCC)=O.[CH3:29][C:30]1[CH:31]=[C:32]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[NH2:33]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:29][C:30]1[CH:31]=[C:32]([NH:33][C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH:34]=[C:35]([CH3:37])[CH:36]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
Commercially available Boc-L-proline (16, 2.3 g; 10.7 mmol) is dissolved in DCM (20 ml) and cooled to 0° C. followed by the addition of NEt3 (1.12 g; 11.22 mmol) and ethyl chloroformate (1.22 g; 11.22 mmol) and finally commercially available 3,5-dimethylaniline (15) (1.36 g; 11.22 mmol). The reaction mixture is stirred at rt for 60 minutes. Brine (50 ml) is added and the organic layer is separated. The aq. layer is extracted with DCM (2×30 ml). The combined organic layers are dried over MgSO4, filtered and the solvent is removed under reduced pressure to give 4.07 g of crude (S)-tert-butyl 2-((3,5-dimethylphenyl)carbamoyl)pyrrolidine-1-carboxylate (17) which is used in the next step without further purification. LC-MS: tR=0.81 min; [M+H]+=319.11.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][N:19]=2)[CH2:13][CH2:12]1)=O.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Na+].O>[C:26]1([C:25]#[C:24][C:21]2[CH:20]=[N:19][C:18]([NH:17][C@H:14]3[CH2:15][CH2:16][C@H:11]([CH2:9][OH:8])[CH2:12][CH2:13]3)=[N:23][CH:22]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of LiAlH4 (17 mg, 0.44 mmol) in 10 ml THF was added at 0-5° C. within 15 min a solution of trans-4-(5-phenylethynyl-pyrimidin-2-ylamino)-cyclohexanecarboxylic acid methyl ester (40 mg, 0.12 mmol) in 5 ml of THF. The reaction mixture was stirred for 30 min at 0-5° C. Saturated NaHCO3 solution and brine were added to the reaction mixture which was extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silicagel (heptane:ethyl acetate 2:1). The desired compound was obtained as a light yellow solid (29 mg, 81%), MS: m/e=308.5 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.[OH:12][C:13]([C@:16]1([N+:32]#[C-:33])[C@@H:19]([CH2:20][CH:21]=[CH2:22])[N:18]([C:23](=[C:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[C:17]1=[O:31])([CH3:15])[CH3:14]>C(Cl)Cl.CC(C)=O.C(O)(=O)C>[CH2:20]([C@@H:19]1[C@:16]2([N:32]=[CH:33][O:12][C:13]2([CH3:14])[CH3:15])[C:17](=[O:31])[N:18]1[C:23](=[C:28]([CH3:30])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH2:22]
Reactant: [C-]#[N+][C@]1(C(C)(C)O)C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=CC[C@H]1N(C(C(=O)OC)=C(C)C)C(=O)[C@@]12N=COC2(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.8 %

Procedure:
A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (17 μl) in methylene chloride (0.1 ml) was added to a solution of methyl 2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (17 mg) in methylene chloride (1 ml) and acetone (1 ml) at 0° C., and the mixture was stirred for 20 hours at ambient temperature. Acetic acid (2 drops) was added to the reaction mixture at 0° C., and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (20 ml), and the solution was washed with 10% aqueous phosphoric acid, brine, phosphate buffer (pH 6.9), aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 2-[(3R,4R)-3-allyl-5,5-dimethyl-1-oxo-2,8-diaza-6-oxaspiro[3,4]oct-7-en-2-yl]-3-methylbut-2-enoate (19 mg) as crude crystals.