Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([N:12]3[CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:21])[CH:18]=4)[C:13]3=[O:22])[C:6]=2[CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[Cl:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:22])[N:12]([C:7]1[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[C:11]=3[CH:10]=[N:9][CH:8]=1)[CH2:20]2
Reactant: NC1CCCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CCCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(8-amino-5,6,7,8-tetrahydro-isoquinolin-4-yl)-5-chloro-2,3-dihydro-isoindol-1-one (156 mg, 0.5 mmol) and Et3N (210 uL) in DCM (10 mL) was added ethanesulfonyl chloride (48 uL mg, 0.5 mmol) at 0° C. and stirring continued at 0° C. for 1 h. The resulting mixture was extracted with EtOAc (2×50 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound. The residue was separated by prep-HPLC to give a racemic mixture of title compound (170 mg, 84%) as a light yellow solid. MS: 406.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[N:38]2[CH:39]=[C:40]([NH2:44])[CH:41]=[C:42]([CH3:43])[C:37]2=[N:36][N:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:44][C:40]2[CH:41]=[C:42]([CH3:43])[C:37]3[N:38]([C:34]([CH3:33])=[N:35][N:36]=3)[CH:39]=2)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:15])[CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn2c(C)nnc12
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(C)c2nnc(C)n2c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.11) and 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4) overnight at RT. tR: 1.02 min (LC-MS 2); ESI-MS: 605 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:24])(=O)=O>ClCCl>[Cl:24][CH2:11][CH:10]=[CH:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC/C=C/C#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCC=CC#Cc1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (4.9 g, 31.0 mmol) and triethylamine (3.8 g, 38.0 mmol) in dry dichloromethane (200 mL) was added methanesulfonyl chloride (3.8 g, 33 mmol) dropwise. Stirring was continued at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue washed with heptane/dichloromethane (×2) to give 4.5 g (82%) crude (E)-(5-chloro-pent-3-en-1-ynyl-benzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([OH:17])(=[O:16])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:9][C:14]([CH2:13][CH2:12][C:11]([OH:17])=[O:16])=[CH:15]2
Reactant: C#CCCC(=O)O
Reactant: Nc1c(F)cc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc2cc(Br)cc(F)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of (4-bromo-2-fluoro-6-iodophenyl)amine (D159) (2 g), 4-pentynoic acid (0.62 g) and copper(I) iodide (0.60 g) in DMF (4 mL) stirred under nitrogen at room temperature was added bis(triphenylphosphine)palladium(II) chloride (0.222 g), then triethylamine (2.2 mL) was added in a portion. The reaction mixture was stirred at 80° C. in microwave reactor for 2 hrs. The solid in the mixture was filtered, the filtrate was diluted with EtOAc (30 mL), washed with brine (80 mL) and water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoic acid (D160) (700 mg) as a yellow solid. MS (ES): C11H9BrFNO2 requires 285; found 286.0 (M+H+). δH (CDCl3, 400 MHz): 2.75 (2H, t), 3.07 (2H, t), 5.45 (1H, s), 7.05 (1H, d), 7.41 (1H, s).
Reaction SMILES: C([N:4]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:57]=[CH:58][CH:59]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:19]([CH2:26][CH2:27][N:28]([CH2:36][CH2:37][C:38]2[C:43]3[O:44][CH2:45][C:46](=[O:48])[NH:47][C:42]=3[C:41]([O:49]C(OC(C)(C)C)=O)=[CH:40][CH:39]=2)C(=O)OC(C)(C)C)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])=[N:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72]>C(Cl)Cl.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>[F:74][C:73]([F:76])([F:75])[C:71]([OH:77])=[O:72].[N:7]1[NH:8][N:4]=[N:5][C:6]=1[C:9]1[CH:10]=[C:11]([CH:57]=[CH:58][CH:59]=1)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:26][CH2:27][NH:28][CH2:36][CH2:37][C:38]1[C:43]2[O:44][CH2:45][C:46](=[O:48])[NH:47][C:42]=2[C:41]([OH:49])=[CH:40][CH:39]=1)=[O:18]
Reactant: C=CCn1nnc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCC3)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1COc2c(CCNCCN(C(=O)CCOCCc3cccc(-c4nn[nH]n4)c3)C3CCCCC3)ccc(O)c2N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(3-(3-(2-allyl-2H-tetrazol-5-yl)phenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Example 15, Step v)] (170 mg), 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (97 mg) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) were dissolved in DCM (2 mL) and sealed into a microwave tube. The reaction was heated to 100° C., over a period of 30 min in the microwave reactor. After cooling to rt, TFA (1 mL) was added and the mixture stirred for 30 min. The mixture was concentrate in vacuo do give a crude product. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound (41.8 mg) as a solid. MS [M+H]+=578.3 (calc=578.3091) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.80 (dt, J=1.6 and 7.4 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.44 (dt, J=1.5 and 7.9 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.46 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 3.74 (t, J=6.5 Hz, 2H), 3.72 (t, J=6.0 Hz, 2H), 3.71-3.63 (m, 1H), 3.48 (t, J=5.8 Hz, 2H), 3.14 (t, J=7.1 Hz, 2H), 3.04 (t, J=5.7 Hz, 2H), 2.94 (t, J=6.3 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 1.79-1.71 (m, 2H), 1.68-1.57 (m, 3H), 1.44-1.23 (m, 4H), 1.16-1.03 (m, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:23]2[C:24]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reaction time: 15 h
Yield: 68.5 %

Procedure:
After adding 123 mg of 4-nitrophenol, 136 mg of potassium carbonate and 1.5 ml of dimethylformamide to 113 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728, and stirring the mixture for 15 hours at 130–135° C., and additional 60 mg of 4-nitrophenol and 75 mg of potassium carbonate were added and the mixture was stirred for 6 hours. After returning the mixture to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the solid obtained by concentration to dryness was washed with ether to obtain 112 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:25]=[C:15]3[NH:16][C:17](=O)[C:18]4[C:23]([N:14]3[N:13]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:25]=[C:15]2[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Nc2nc3[nH]c(=O)c4ccccc4n3n2)cc1OC
Product: COc1ccc(Nc2nc3nc(Cl)c4ccccc4n3n2)cc1OC
Temperature: 90 °C

Procedure:
A suspension of 2-(3,4-Dimethoxy-phenylamino)-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one (57 mg) in phosphorus oxychloride (5 mL) was heated at 90° C. for 2 h. Evaporation. The residue was suspended in dichloromethane, washed with cold sodium bicarbonate, brine and dried (Na2SO4). Filtration and concentration gave crude (5-Chloro-[1,2,4]triazolo[1,5-a]quinazolin-2-yl)-(3,4-dimethoxy-phenyl)-amine (68 mg). LC-MS: m/e=356.1 (M+H),
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)[CH3:2].C([Li])CCC.[C:14](OCC)(=[O:16])[CH3:15]>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][C:14]([CH3:15])=[O:16])[S:6][CH:7]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCc1csc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1csc(CC(C)=O)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1.70 g (13.4 mmol) of the compound from example 16A are dissolved in 15 ml of abs. THF and, at −78° C., 5.88 ml (14.7 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 2.00 g (22.7 mmol) of ethyl acetate are added as a solution in 10 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. 1.89 g (84% of theory) of the title compound are obtained. GC-MS (Method 2): Rt=4.20 min; MS (Elpos): m/z=169 [M]+.
Reaction SMILES: Cl[CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]([N:5]([CH2:15][C:16]1([OH:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+]>CN(C=O)C.O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:5]2[CH2:15][C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[O:29][CH:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:3]2=[O:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(Cl)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC(c3ccccc3)C2=O)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a suspension of tert-butyl 4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (322 mg, 0.64 mmol) in DMF (3 mL) at 0° C. was added NaH (27 mg, 0.67 mmol). The reaction mixture was allowed to warm to room temperature overnight, then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 0-40% EtOAc/DCM to give tert-butyl 10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (215 mg, 72%) as a colorless oil. ESI-MS m/z calc. 502.2. Found 503.5 (M+1)+; Retention time: 1.90 minutes (3 min run).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:46][C:47]([CH3:51])([CH3:50])[CH:48]=[O:49]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:48]([OH:49])[C:47]([CH3:51])([CH3:50])[CH3:46])=[CH:23][C:22]=2[CH3:28])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Reactant: CC(C)(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)C(C)(C)C)ccc1-c1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: -78 °C

Procedure:
2 g (3 mmol) of 3′-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]-4-bromo-2-methylbiphenyl are dissolved in 30 mL of anhydrous THF and the mixture is cooled to −78° C. 1.4 mL (3.5 mmol) of 2.5 M butyllithium are added slowly and the mixture is maintained at −78° C. for 1 hour. 400 mL (3.7 mmol) of 2,2-dimethylpropionaldehyde are added dropwise and the medium is warmed slowly to room temperature and then treated according to the usual treatment. The desired product is obtained in the form of a colourless oil (m=2 g; Y=100%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14](=[O:35])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[O:26])=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][NH:27][C:25](/[CH:24]=[CH:23]/[C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[CH:15]/[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[O:35])=[CH:18][CH:19]=1)=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1)NOC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Methanesulfonyl chloride (0.41 ml, 5.3 mmol) was added to a stirred solution of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (1.08 g, 2.68 mmol) and TEA (1.47 ml, 10.6 mmol) in DCM (18 ml) and DMF (12 ml). The mixture was stirred at room temperature for 30 min and then brought to basic conditions with 5% NaHCO3. The resulting slurry was extracted with Et2O and the organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 1:1) to give 600 mg of a mixture of the title compound and (E)-3-{4-[(E)-3-(3-chloromethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as the main product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][O:28][CH2:29][CH:30]([NH:32][C:33]1[NH:37][C:36]([CH3:38])=[N:35][N:34]=1)[CH3:31]>>[CH3:27][O:28][CH2:29][CH:30]([N:32]1[C:17](=[O:18])[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:34]2[N:35]=[C:36]([CH3:38])[N:37]=[C:33]12)[CH3:31]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: COCC(C)Nc1nnc(C)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)COC)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.84 g) and N-(2-methoxy-1-methylethyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.4 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:2]=1.[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:15]([NH:21][C:22]([N:11]1[CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN=C=O
Reactant: O=c1[nH]cc(-c2cccnc2)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCCNC(=O)n1cc(-c2cccnc2)c(=O)[nH]c1=O
Yield: 57 %

Procedure:
The title compound was obtained according, to the procedure described for the synthesis of Example 1, starting from 5-(3-pyridyl)-1H-pyrimidine-2,4-dione (0.067 g, 0,198 mmol). Herein, 2 equivalents of DMAP and 2.7 equivalents of hexyl isocyanate in 4 mL pyridine were used. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 40:60) to afford the title compound (0.04 g, 57%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=6.0 Hz, 3H), 1.29-1.41 (m, 6H), 1.58-1.67 (m, 2H), 3.42 (dt, J=7.1, 5.5 Hz, 2H), 7.37 (ddd, J=8.0, 4.9, 0.9 Hz, 1H), 7.97 (td, J=8.0, 2.0 Hz, 1H), 8.64 (dd, J=4.9, 1.7 Hz, 1H), 8.66 (s, 1H), 8.80 (dd, J=2.4, 0.9 Hz, 1H), 9.11 (t, J=5.0 Hz, 1H), 9.21 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 14.13, 22.66, 26.64, 29.29, 31.51, 41.58, 77.16, 113.74, 123.50, 127.93, 136.39, 136.58, 148.70, 149.48, 149.74, 151.09, 161.30. MS (ESI) m/z: 317 (M-Hr.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]>C(Cl)Cl>[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C

Procedure:
Morpholine (2.2 ml, 25 mmol) was slowly added to 3-Nitro-benzenesulfonyl chloride (5.5 g, 25 mmol) in CH2Cl2 at 0° C. The reaction was warmed up to rt in 0.5 h. After CH2Cl2 was removed in vacuo, saturated NaHCO3 solution was added and the solid was filtered and dried to give 4-(3-Nitro-benzenesulfonyl)-morpholine as an off white solid (5.9 g, 87%). MS (ESI) m/z=273 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=[O:17])#[N:2].[OH-].[K+].O.Cl>C(O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:16]([OH:18])=[O:17])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2cccc(C#N)c2)c1C#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(-n2ncc(C(=O)O)c2C#N)c1
Yield: 62.4 %

Procedure:
Approximately 7.7 g of 5-cyano-1-(3-cyanophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester was dissolved in 75 ml of hot ethanol. To the reaction mixture was added 3.2 g of potassium hydroxide dissolved in ethanol. A small amount of water was added to the reaction mixture which was immediately poured into water. The solution was then acidified with concentrated hydrochloric acid and the precipitated solid was collected by filtration and dried to provide 4.3 g of 5-cyano-1-(3-cyanophenyl)-1H-pyrazole-4-carboxylic acid. MP=190°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2=[N:9][C@@H:10]([CH2:24][C:25]([O:27]C)=[O:26])[C:11]3[N:12]([C:20]([CH3:23])=[N:21][N:22]=3)[C:13]3[S:17][C:16]([CH3:18])=[C:15]([CH3:19])[C:14]2=3)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2=[N:9][C@@H:10]([CH2:24][C:25]([OH:27])=[O:26])[C:11]3[N:12]([C:20]([CH3:23])=[N:21][N:22]=3)[C:13]3[S:17][C:16]([CH3:18])=[C:15]([CH3:19])[C:14]2=3)=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Methyl 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate (see e.g., WO 2006129623) (100.95 mg, 0.243 mmol was suspended in 1 mL methanol to which was added a freshly prepared solution of lithium hydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambient temperature for 3 hours. The methanol was evaporated and the pH adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and extracted four times with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and evaporated to afford 2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (85.3 mg, 87.0%); ESI-MS m/z=401.1 [(M+H)+] which was used directly in the next reaction.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[CH3:31]>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[CH:24][C:23]=1[CH3:31]
Reactant: Cc1cc(C(=O)O)ccc1Cl
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: Cc1cc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)ccc1Cl

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-chloro-3-methylbenzoic acid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][O:5][CH2:4]1.C1COCC1.Cl>O>[CH3:1][O:2][C@@H:3]1[C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@H]1COCCC1(OC)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1COCCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A 5-L 4-neck round bottom flask equipped with a overhead air stirrer, nitrogen inlet adapter, thermocouple, and septum was charged with (S)-3,4,4-trimethoxytetrahydro-2H-pyran (as prepared in the previous step, 83 g, 0.47 mol), THF (2.1 L), H2O (670 mL), and stirred in ice/acetone bath until <0° C., where upon a solution of HCl (conc., 350 mL, 4.24 mol) was added via addition funnel over 30 min while keeping temperature <2° C. After the addition was complete, the reaction was allowed to stir for 1 h at 0° C. The reaction was evaporated until ˜1.2 L of concentrate remained. The concentrate was transferred to a reparatory funnel and extracted with CH2Cl2 (3×750 mL). The combined organic fractions were washed with sat. NaHCO3 (500 mL), brine (500 mL), dried over MgSO4, filtered and evaporated to afford the title compound (46.9 g, 77%, Chiral GC 91% ee) as an oil which solidified upon sitting. Optical Rotation: [α]25(D)+3.65° (c=1.020, MeOH); Elemental Analysis calc for C6H10O3: C, 53.39; H, 7.57. Found: 53.59; H, 7.62.