Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Li]CCCC.[B:23]([O:32]C(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1>[C:14]([S:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][C:8]=1[O:24][B:23]([OH:32])[OH:28])(=[O:13])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCc1ccc(NS(=O)(=O)C(C)(C)C)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(NS(=O)(=O)C(C)(C)C)c(OB(O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-n-propylphenyl-t-butylsulfonamide (2.85 g, 11.2 mmoL) in anhydrous THF (20 mL) cooled to -40° C. under N2 was added 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to rt and stirred for 2 h. To the mixture, containing the bright red dianion at 0° C., was added B(OiPr)3 (3.9 mL, 1.5 equiv). The next day 2N HCl (3 mL) was added and the mixtue was stirred for 1 h. The solvent was removed under reduced pressure and the residue was extracted With EtOAc. The organic was washed with 2N HCl, H2O and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. Rf=0.5 (1:1 EtOAc/Hex). The crude material was used in subsequent steps without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([CH:30]([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:30]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(Cc1ccccc1)c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1ccccc1)c1ccccc1
Yield: 68 %

Procedure:
The title compound was prepared in a yield of 68% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1,2-diphenylethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].[OH:25][CH2:26][CH:27]([NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32])[CH2:28][OH:29]>>[OH:25][CH2:26][CH:27]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32])[CH2:28][OH:29]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Br)s1
Product: O=S(=O)(NC(CO)CO)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.54) (158 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (230 mg, 80%). MS (ISN) 571.0 [(M−H)−]; mp 153° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH3:32][O:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[C:6]=2[N:20]=1)[C:26]([OH:28])=[O:27]
Reactant: CC1CCCC1N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1C)CCC(=O)N2C
Yield: 68.2 %

Procedure:
A mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-5-methyl-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-57), 0.06 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.087 g of (rac)-3-methoxy-4-[5-methyl-9-(2-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-57a) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]([C:4]1([CH3:23])[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](Cl)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(CC)CC)C.[CH2:31]([NH2:34])[CH2:32][CH3:33].C(OCC)(=O)C>CN(C=O)C>[OH:1][CH:2]([C:4]1([CH3:23])[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:34][CH2:31][CH2:32][CH3:33])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: CCCN
Reactant: CC(O)C1(C)C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCNC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C)(C(C)O)C2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (50 mg) in anhydrous DMF (1 ml) is cooled in an ice-bath and stirred while triethylamine (28 μl) and propylamine (12.4 μl) are added. The resulting solution is allowed to slowly warm to room temperature and kept at room temperature for 1 hr. The solution is diluted wiht ethyl acetate (10 ml), washed with water (5×2 ml), pH 3 phosphate buffer (2 ml), 5% NaHCO3 (2 ml), and brine, dried with MgSO4, filtered, and evaporated in vacuo to give benzyl 6-(1-hydroxyethyl)-6-methyl-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C(Cl)(=O)C.[Na+].[I-:15]>C(#N)C>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([I:15])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1cc(Br)cnc1I
Yield: 94.8 %

Procedure:
To a stirred solution of 2,5-dibromo-3-methyl-pyridine (20.0 g, 79.7 mmol, 1 eq) in acetonitrile (120 mL) was added acetyl chloride (8.5 mL, 119.5 mmol, 1.5 eq) followed by addition of NaI (47.8 gm, 319 mmol, 4 eq) at room temperature. Resulting reaction mixture was refluxed for 16 hours. After complete consumption of starting material, reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3×200 mL). Organic layer was washed with aqueous sodium bicarbonate (2×300 mL), brine (300 mL) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown oil (35.5 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 5% EtOAc in hexane to get title compound as brown oil (22.5 g, 94.78%). 1H NMR (400 MHz, CDCl3) δ: 2.36 (s, 3H), 7.56 (d, J=2.4 Hz, 1H), 8.24 (d, J=2.28 Hz, 1H). LC-MS (m/z): 297.9 (M+H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:19])[C:17]1[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=1)([OH:10])=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 75 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
A solution of 8.6g (0.063 mole) of anthranilic acid in 50 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 150 ml of 1,2-dimethoxyethane. The reaction mixture was heated at approximately 75° C. for 30 minutes after which time it was stirred for 48 hours at room temperature. The reaction mixture was then filtered, and the filtrate was evaporated to give the crude product as an oil. This oil was triturated with a mixture of ethanol and water to give a solid which was recrystallized twice from a mixture of ethanol and water to give 5.3g of white crystalline N-(2-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 202°-203° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 71.4; %H, 7.5; %N, 3.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:18]([NH:20][C:21]([NH2:23])=[NH:22])#[N:19]>C(OCCOCCO)C>[NH2:23][C:21]1[N:20]=[C:18]([NH2:19])[C:15]2[CH2:16][CH:11]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)([CH3:10])[CH3:9])[CH2:12][CH2:13][C:14]=2[N:22]=1
Reactant: N#CNC(=N)N
Reactant: CC(C)(c1cccc(Cl)c1)C1CCC(=O)CC1
Solvent: CCOCCOCCO
Product: CC(C)(c1cccc(Cl)c1)C1CCc2nc(N)nc(N)c2C1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.2 grams (0.013 mole) of 4-[2-(3-chlorophenyl)propan-2-yl]cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-[2-(3-chlorophenyl)propan-2-yl]-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].CO.CCOC(C)=O>C1(OC2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=12
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A mixture of 5 (1.65 g, 6.85 mmol), potassium carbonate (5.68 g, 41.1 mmol) and 2-fluoro-4-nitrophenol (1.65 g, 10.3 mmol) were heated to 170° C. in diphenyl ether (20 mL) for 5 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography (eluents EtOAc-hexane 9:1, then MeOH-EtOAc 1:4) to afford 6 as a yellow solid (1.02 g, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (d, J=5.3 Hz, 1H), 8.46 (dd, J=2.8 and 10.3 Hz, 1H), 8.20 (ddd, J=1.3 and 2.6 and 9.0 Hz, 1H), 7.98 (s, 1H), 7.73 (dd, J=8.3 Hz, 1H), 6.99 (dd, J=0.9 and 4.8 Hz, 1H), 3.25-3.30 (m, 3H), 3.02-3.11 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:18])[CH:15]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BrH:19]>C(OCC)(=O)C.C(O)(=O)C.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:18])[CH2:15][Br:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)CBr
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 2-(2-diazo-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.51 g, 2.0 mmol) in dry ethyl acetate (11 mL) was cooled to −45° C. and treated with a 33% solution of hydrobromic acid in acetic acid (0.24 mL), which was added dropwise over 45 min. The cold reaction mixture was diluted with tert-butyl methyl ether (34 mL) and left to warm to room temperature. The mixture was washed twice with saturated sodium hydrogenocarbonate (2*11 mL) and with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 2-(2-bromo-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.28 g, 45%) as a light yellow oil, MS (ISP): 306.1, 308.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:4]2[CH2:5][CH2:6][NH:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]2)=[N:13][CH:14]=1)#[N:17]
Reactant: COC(=O)C1CNCCN1
Reactant: N#Cc1ccc(Cl)nc1
Product: COC(=O)C1CN(c2ccc(C#N)cn2)CCN1
Yield: 35 %

Procedure:
This compound was synthesized from methyl piperazine-2-carboxylate and 6-chloronicotinonitrile as described for example 39 step 1 (90 mg, yield 35%). 1H NMR (400 MHz, MeOD) δ 8.42 (dd, J=2.4 Hz, 0.6 Hz, 1H), 7.76 (dd, J=9.0 Hz, 2.3 Hz, 1H), 6.90 (m, 1H), 4.39-4.35 (dd, J=13.2 Hz, 2.6 Hz, 1H), 3.95-3.90 (m, 1H), 3.76 (s, 3H), 3.63-3.60 (dd, J=8.4 Hz, 3.4 Hz, 1H), 3.52-3.47 (dd, J=13.1 Hz, 8.4 Hz, 1H), 3.45-3.39 (ddd, J=13.1 Hz, 9.3 Hz, 3.4 Hz, 1H), 3.13-3.08 (m, 1H), 2.86-2.79 (ddd, J=12.5 Hz, 9.1 Hz, 3.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[F:40][C:41]1[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43][N:42]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:45]3[CH:44]=[CH:43][N:42]=[C:41]([F:40])[CH:46]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4ccnc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 2-fluoropyridine-4-boronic acid (40 mg, 0.27 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture, 0.4 ml of aqueous sodium carbonate (1M) was added, followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, and the residue was dissolved in 2.5 ml of methanol. The product was purified with Preparative HPLC to give 70 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1](=[O:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC=C/C=C/CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCC=C/C=C/C=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 45.7 %

Procedure:
To a solution of trans, trans-2,4-nonadien-1-ol (20 g) in chloroform (400 ml) was added manganese dioxide (125 g). The mixture was stirred for 11 hours at ambient temperature and then filtered. The filtrate was concentrated under reduced pressure to give an oily residue, which was subjected to a column chromatography on silica gel (developing solvent: chloroform). The eluate was concentrated under reduced pressure to give colorless oily trans, trans-2,4-nonadienal (9 g).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3,4-dichlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 274°-276° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].[BH3-]C#N.[Na+].CC(O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][NH:19][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15]
Reactant: COC(CN)OC
Reactant: Cc1c(C=O)cc(Br)cc1OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(CNCc1cc(Br)cc(OC(C)C)c1C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of 5-bromo-2-methyl-3-(propan-2-yloxy)benzaldehyde (108b, 4.5 g, 18 mmol) and 2,2-dimethoxyethanamine (2.2 g, 21 mmol) in MeOH (50 mL) was added NaBH3CN (1.4 g, 22 mmol) and HOAc (1 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL). The reaction mixture was concentrated under vacuum. The residue was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=5:1) to obtain N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-2,2-dimethoxyethanamine (108c, 3.5 g, 58%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Cl-].C([Al+]CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[NH:8][CH:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc2cc[nH]c2cc1Cl
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc2c(C(C)=O)c[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of methyl 6-chloro-1H-indole-5-carboxylate (0.5 g, 2.4 mmol) in dichloromethane at 0 C, was added drop-wise, a solution of diethyl aluminum chloride (3.6 mL, 1M) and stirred under nitrogen for 45 min. To this mixture, added a solution of acetyl chloride (0.3 g, 3.8 mmol) in dichloromethane (3 mL). The resulting mixture was stirred for 3 h and at room temperature for 30 min. The reaction was quenched by the addition of cold Tris buffer (pH 7.5, 1 mM and added dichloromethane (2×15 mL). The solid that separated was removed by filtration, washed with water and dried to give the title compound (0.44 g, 73%), m/z=252 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([CH3:42])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:40])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:10][C:9]=1[CH3:41])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:42][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:25]2[S:29][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=3)=[N:27][C:26]=2[CH3:40])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:10][C:9]=1[CH3:41])([CH3:6])[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2cccc(OC)c2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CN(Cc2ccc(OC(C)(C)C(=O)O)c(C)c2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of example 96 (450 mg, 0.29 mmol) in EtOH (20 mL) was added 1N NaOH (0.9 mL, 3 eq.) and the reaction was stirred at 85° C. for 1 h. When all of the starting material had disappeared, the reaction cooled, evaporated to dryness, taken up with 1N HCl, extracted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed eluting with CH2Cl2 (100%) to afford the title compound as a yellow solid (60 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:30])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Fc1ccccc1C1=CCC(=S)Nc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
20.2 g of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one are dissolved in 110 ml of hexamethylphosphoric acid triamide and treated with 13.8 g of 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide. The mixture is warmed to 100° for 1 hour, again cooled to room temperature and poured into 2.2 l of water. The mixture is extracted three times with ethyl acetate and the organic extracts are washed with water, sodium hydrogen carbonate solution and with saturated sodium chloride solution. The ethyl acetate solutions are evaporated and the residue is chromatographed on 400 g of silica gel. By elution with toluene and toluene/chloroform (19:1) and recrystallization of the resulting material from diisopropyl ether there is obtained 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepine-2-thione of melting point 179°-181°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[N:25]1([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@H:11]2[CH2:15][N:14]([C:34]([C:31]3([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:32][CH2:33]3)=[O:35])[C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Cl)cc3)CN2)CC1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Cl)cc3)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 46 %

Procedure:
The reaction of (2S,4R)-4-(4-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7B with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-4-(4-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light yellow viscous oil (46%). MS ISP (m/e): 505.2/507.2 [(M+H)]+.