Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:19])[C:16]([OH:18])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:20]([NH:24][C:16](=[O:18])[C:15]([NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:13][CH:12]=[N:11][CH:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: COc1cc(NC(=O)C(=O)O)ccc1-c1cnco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)C)ccc1-c1cnco1
Yield: 34.7 %

Procedure:
A solution of 26 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamic acid, 15 mg (0.2 mmol) of tertiary butylamine, 28 mg (0.15 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 15 mg (0.11 mmol) of 1-hydroxy-7-azabenzotriazole in 1 ml of dimethylformamide was stirred at room temperature for 4 hours then diluted with ethyl acetate and washed with 2M hydrochloric acid, saturated sodium bicarbonate and water. The resulting solution was dried over magnesium sulphate and evaporated to dryness. The residue was triturated with diethyl ether/petrol (1:1) and collected by filtration to give 11 mg of N-tert-butyl-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 318.0 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:8]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:26][NH2:27].C(Cl)Cl>C1COCC1>[CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:8][NH:27][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S,3S)-3-cyclopentyl-3-hydroxy-2-(1,3-dioxoisoindolin-2-yl)propanal (1.339 g, 4.7 mmol) in dry THF (20 mL) was cooled to 0° C. Acetic acid (2.5 mL, 44 mmol), methylamine (33% in EtOH, 2.5 mL, 20 mmol), and NaHB(OAc) 3 (4.4937 g, 21.3 mmol) were added sequentially in single portions. The ice bath was removed and the mixture was stirred for 2 h at rt. The solvent was stripped and the crude 2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione was used directly in the next step. LC-MS (3 min) tR=1.07, m/z=303 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a solution of 4-(3-chloro 4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide as a yellow solid (89 mg, 72%).
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.Cl>CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:18])[CH2:17][O:14][CH2:15]1
Reactant: O=C1COC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)COC1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
Tetrahydrofuran (110 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (7.18 mL, 48.6 mmol) was then added and stirred under N2 and then cooled to 0° C. oxetan-3-one (2.5 g, 34.7 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.347 mL, 0.347 mmol) was added dropwise slowly via syringe and allowed to warm up to RT for 1 hr. The reaction was then cooled back down to 0° C. and added 30 mL of 1N HCl and stirred at RT for overnight. The reaction was then diluted with EtOAc and separated with water. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give the product 3-(trifluoromethyl)oxetan-3-ol (2.00 g, 40.6% yield) as an orange thin oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.82-4.74 (m, 2H), 4.70-4.60 (m, 2H), 3.23 (br. s., 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][N:11]1[C:15]([C:16](=O)[C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:14][CH:13]=[N:12]1>CO>[OH:3][N:2]=[C:16]([C:15]1[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=1)[C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1
Reactant: NO
Reactant: Cn1nccc1C(=O)C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1nccc1C(C#Cc1ccc(C(F)(F)F)cc1)=NO
Reaction time: 8 h
Yield: 87.6 %

Procedure:
An aqueous solution (3.0 mL) of hydroxylamine hydrochloride (338 mg) and an aqueous solution (4.0 mL) of sodium carbonate (515 mg) were added to a methanol (40 mL) solution of 1-(1-methyl-1H-pyrazol-5-yl)-3-[4-(trifluoromethyl)phenyl]prop-2-yn-1-one (338 mg) at a room temperature, and the obtained solution was then stirred overnight. Thereafter, the reaction solution was concentrated under a reduced pressure, and water was then added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=10:0 to 5:5), so as to obtain the title compound (312 mg) in the form of a yellow oily substance.
Reaction SMILES: C[CH:2]([CH2:11][CH2:12][CH:13]=C(C)C)[CH2:3][CH2:4][CH2:5][C:6](=[O:10])[C:7]([O-:9])=[O:8].O=C(CCC)C(O[CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=O.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.C1(C(=O)C(OC2CCCC2CCCCC)=O)CCCCC1.CC(CC)C(=O)C(OCCC(C)CCC=C(C)C)=O.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O.C1(C(=O)C(OCCCCCCCCCC)=O)CCCCC1.CC(CC)C(=O)C(OC/C=C(\C)/CCC=C(C)C)=O.C(C1C=CC(C(=O)C(OCCC(C)CCC=C(C)C)=O)=CC=1)(=O)C>>[CH:11]12[CH2:2][CH:3]([CH2:13][CH2:12]1)[CH2:4][CH:5]2[C:6](=[O:10])[C:7]([O:9][CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[O:8]
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Reactant: CCCC(=O)C(=O)OCCC(C)CCC=C(C)C
Agent: CC(=O)c1ccc(C(=O)C(=O)OCCC(C)CCC=C(C)C)cc1
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1
Product: CC(C)=CCCC(C)CCOC(=O)C(=O)C1CC2CCC1C2

Procedure:
MS (EI): 288 (1); 183 (4); 168 (1); 155 (1); 139 (2); 138 (15); 137 (2); 124 (3); 123 (30); 122 (2); 121 (1); 110 (1); 109 (5); 97 (1); 96 (11); 95 (100); 93 (4); 91 (1); 83 (4); 82 (19); 81 (21); 80 (5); 79 (3); 77 (2); 70 (2); 69 (23); 68 (5); 67 (22); 66 (3); 65 (3); 57 (3); 56 (3); 55 (15); 54 (2); 53 (5); 43 (4); 42 (3); 41 (33); 39 (6); 29 (5); 28 (1); 27 (5).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[C:5]21[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]3[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12]=32)=[CH:7][CH:8]=1
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCCC1
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCCC1
Reaction time: 0.75 h
Yield: 83 %

Procedure:
A solution of 2.56 g of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 2:3). 2.45 g (83%) of (R)-1-[7'-methyl-1',4'-dihydro-spiro[cyclohexane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)[CH:8]=2)=[C:4]([F:30])[CH:3]=1.FC1C=C(N[C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=2)=[O:58])C=CC=1OC1C=CN=C(NCCN2CCOCC2)C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(CNC2N=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=CN=2)=CC=1>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]4[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=4)=[O:58])=[CH:3][C:4]=3[F:30])[CH:8]=2)=[CH:19][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Yield: 87.5 %

Procedure:
The title compound was prepared from a mixture 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine (45 mg, 0.11 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 24 mg, 0.12 mmol), TBTU (48 mg, 0.15 mmol), DIPEA (0.26 mL, 0.15 mmol), and DMF (1 mL) using a similar procedure described for the preparation of Compound C of Example 1. The crude product was triturated with isopropyl ether to give the title compound (56 mg, 88%) as a pink solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.27 (s, 1H), 9.45 (s, 1H), 8.25 (s, 1H), 7.77 (dd, 1H, J=12.7, 2.0 Hz), 7.65-7.62 (m, 2H), 7.46 (d, 4H, J=7.3 Hz), 7.40 (dd, 2H, J=7.6, 7.3 Hz), 7.37-7.29 (m, 3H), 7.17 (dd, 2H, J=9.0, 8.3 Hz), 7.00 (d, 2H, J=9.0 Hz) 6.09 (s, 1H), 5.09 (s, 2H) 3.49 (s, 2H); MS(ESI+) m/z 582.3 (M+H)+.
Reaction SMILES: OC/C(/C)=C/CC/C(/C)=C/CN(CC)CC.C(Cl)Cl.[CH3:20][C:21]([OH:30])([CH2:23][CH2:24][CH2:25][C:26]([CH:28]=[CH2:29])=[CH2:27])[CH3:22]>>[CH3:27]/[C:26](/[CH:28]=[CH2:29])=[CH:25]\[CH2:24][CH2:23][C:21]([OH:30])([CH3:20])[CH3:22]
Reactant: C=CC(=C)CCCC(C)(C)O
Agent: CCN(CC)C/C=C(\C)CC/C=C(\C)CO
Solvent: ClCCl
Product: C=C/C(C)=C/CCC(C)(C)O
Reaction time: 0.58 h

Procedure:
Into a 300-ml reactor equipped with a rectifying column (with an estimated number of theoretical plates of 10) filled with "Helipack" was charged 103 g (0.454 mol) of hydroxygeranyl diethylamine. The atmosphere was replaced with nitrogen. 33.6 ml (0.908 mmol) of the above-mentioned methylene chloride solution was added, and the reactants were heated under a reduced pressure of 1 mmHg. About 35 minutes after the reactant temperature in the flask had reached 150° C., distillation was started at a column top temperature of 63° C. After carrying out the reaction for 5 hours, a mixture of myrcenol and ocimenol was obtained in an amount of 59.4 g. The results from gas chromatography indicated that the mixture was composed of 87.6% of myrcenol and 12.4% of ocimenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1conc1-c1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1conc1-c1ccc(F)cc1
Temperature: -10 °C
Yield: 53.9 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid (40 g, 193 mmol) in THF (400 mL) at −10° C. was added triethylamine (27.1 mL, 193 mmol) and then a solution of ethylchloroformate (18.8 mL, 193 mmol) in THF (120 mL) added keeping the temperature below −5° C. After 1 h the mixture was filtered and the filtrate cooled to −10° C. and a suspension of sodiumborohydride (19 g, 483 mmol) in water (120 mL) added over 15 minutes keeping the temperature below −5° C. The mixture was then allowed to warm up to room temperature over 2 h and diluted with aqueous sodium hydroxide (1 N, 700 mL) and extracted with tert-butylmethylether. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1) afforded the title product (20.1 g, 54%) which was obtained as white solid. MS: m/e=194.1 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[CH:1]([C:4]1[C:12]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(O)C(C)C
Temperature: 0 °C
Yield: 68 %

Procedure:
2.5 g (10.76 mmol) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one was dissolved in MeOH (50 ml) (charcoal filtration) and cooled to 0° C. NaBH4 (570 mg, 15.06 mmol) was added portion wise. The reaction mixture was heated to reflux until complete conversion of starting material (2-4 hours). The reaction mixture was cooled to room temperature, and was quenched by the addition of water (50 ml). The aqueous layer was extracted four times with dichloromethane. The combined organic layers were washed with brine, treated with charcoal, dried over Na2SO4, and the solvent was evaporated under reduced pressure. Flash column chromatography (hexanes-ethyl acetate, 5:2; 10% deactivated silica) of the residue (yellow oil) afforded 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol as a colorless oil (1.7 g, 68%), which crystallized upon trituration with pentane; m.p. 69° C. Compound 1002.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Reactant: N#Cc1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Temperature: 200 °C
Yield: 89 %

Procedure:
1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 1) (50 mg, 0.177 mmol), 5-chloropyrazine-2-carbonitrile (37.0 mg, 0.265 mmol) and DIPEA (0.123 mL, 0.706 mmol) were combined in NMP (1.5 mL) and heated in a sealed flask under microwave irradiation to 200° C. for 1 h. The mixture was partitioned between water (150 mL) and EtOAc (4×100 mL). The organic layers were combined, washed with brine (2×100 mL), dried by passing through a hydrophobic frit, and concentrated in vacuo. The resulting residue was purified by chromatography (25 g column, EtOAc/cyclohexane gradient) to give 5-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile (61 mg, 0.158 mmol, 89% yield) as a brown gum.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][C:20]([CH3:24])([CH3:23])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)C)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at the boiling temperature for 24 hours with 1.46 ml (12 mmol) of 3,3-dimethyl-1-butyne, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. After evaporation of the reaction mixture the residue was taken up in methylene chloride and washed twice with water. The organic phase was dried over magnesium sulphate, evaporated and the residue was chromatographed on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1). After crystallization from ethyl acetate and hexane there was obtained 7-chloro-3-(3,3-dimethyl-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 126°-128°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=2[N:17]=1.C1CCC(=C(F)CNCC2C=CC(F)=CC=2)CC1.[H-].[Na+].Cl[CH2:39][CH2:40][S:41][CH3:42]>O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:39][CH2:40][S:41][CH3:42])[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=2[N:17]=1
Reactant: CSCCCl
Reactant: O=C1Nc2ccc(Cl)nc2Oc2ccccc21
Agent: FC(CNCc1ccc(F)cc1)=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSCCN1C(=O)c2ccccc2Oc2nc(Cl)ccc21
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To as suspension of 17.0g (0.069 mole) 2-Chloropyrido[2,3-b][1,4]benzoxazepin-6(5H)-one and 150 mL of N,N-dimethylacetamide was added 9.8g of sodium hydride (50%). The mixture was warmed to 60° C. for 30 minutes. To the reaction mixture 12.2g (0.11 mole) of 2-chloroethylmethylsulfide was added dropwise. The mixture was heated to 120° C. for 4 hours, then cooled to room temperature and poured into water. The crude product was purified by column chromatography using silica gel and then recrystallized from petroleum ether/benzene to yield 17.3g (78% yield) of 2-chloro-5-(methylthioethyl)pyrido[2,3-b][1,4]benzoxazepin-6(5H)-one, m.p. 126°-128° C.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>C1(C)C=CC=CC=1>[C:2]1([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.6 %

Procedure:
A solution of trityl chloride (Aldrich) (5.0 g, 17.9 mmol) and methyl thioglycolate (2.1 mL, 23.3 mmol) in 50 mL of toluene is heated at reflux overnight. The reaction solution is cooled and concentrated in vacuo. The oily residue is crystallized from ethyl acetate/hexane to give 5.4 g (87%) of methyl [(triphenylmethyl)thio]acetate: melting point 111°-115° C.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:20]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH2:16][C:17]#[N:18])=[CH:14][C:9]=2[CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:20][C:21]=1[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2ccc(CCC#N)cc2CC(C)C)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
2.37 ml (2.37 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 275.6 mg (0.79 mmol) 3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73) in 25 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 10 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 174.9 mg (0.52 mmol, 65.99%) 3-(4′-Hydroxy-2,3′-diisobutyl-biphenyl-4-yl)-propionitrile (74) as an oily white solid. Rf (hexanes/EtOAc (2+1)) =0.38. 1H-NMR (500 MHz, CDCl3): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH3), 0.92 (d, 6H, J=6.62 Hz, 2*CH3), 1.63 (m, 1H, CH), 1.93 (m, 1H, CH), 2.45 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.25 Hz, CH2), 2.62 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.94 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.60 (s, br., 1H, OH), 6.75 (d, 1H, J=8.36 Hz), 6.92-6.96 (m, 2H), 7.01-7.06 (m, 2H), 7.11 (d, 1H, J=7.57 Hz). MS (EI): m/z=336 (24), 335 (100), 292 (18), 251 (10), 236 (35), 209 (12), 196 (10), 195 (48), 178 (10), 165 (10). HR-MS (EI): Calcd. for C23H29NO: 335.224914. Found: 335.225330.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnccc1N
Reaction time: 0.75 h
Yield: 92.8 %

Procedure:
Methyl 4-(Boc-amino)pyridine-3-carboxylate (2.38 g, 9.4 mmol) was dissolved in TFA (20 mL) and the solution was allowed to stir for 45 min. The solvent was removed in vacuo and the residue was partitioned between 25% isopropanol in chloroform and satd aq sodium bicarbonate. The layers were separated and the aqueous phase was extracted again with 25% isopropanol in chloroform. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give a solid which was washed with diisopropyl ether and dried in vacuo to give the title compound (1.327 g, 92%) as an off-white solid.