Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:21][CH:20]=[C:19]([CH3:22])[N:9]2[C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3)c(=O)n12
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3ccccc3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.044 g, 0.14 mmol) in tetrahydrofuran (0.4 mL) and water (0.102 mL) was added 1.0 M of trimethylphosphine in tetrahydrofuran (0.17 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added EtOAc and the mixture was extracted twice with 1 N HCl. The combined extracts were neutralized with solid sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step (36 mg, 89.3%). LCMS calculated for C15H16N3OS (M+H)+: m/z=286.1. Found: 286.0.
Reaction SMILES: P(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:28]=[CH:27][C:9]2[C:10]3[C:25](=[O:26])[NH:24][CH2:23][C:11]=3[CH2:12][N+:13]([O-])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]2[C:10]3[C:25](=[O:26])[NH:24][CH2:23][C:11]=3[CH2:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:7]=1
Reactant: O=C1NCC2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: O=C1NCC2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In one portion, 2 ml (2.3 mmol) of phosphorous trichloride were added to a solution of 1.0 g (2.7 mmol) of 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepine-1(2H)-one-5-oxide in 200 ml of methylene chloride and refluxed for 1 hour. The mixture was concentrated at reduced pressure. The residue was dissolved in methylene chloride and neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a dark red residue. Purification of the residue by column chromatography (silica gel, 20 g; eluent, 5% methanol in methylene chloride) followed by crystallization from ethyl acetate gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one as pale yellow prisms solvated with 0.5 mole ethyl acetate, mp 195°-197° C.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:8]2[C:9](=[O:14])[NH:10][C:11](=O)O[C:7]=2[CH:6]=[CH:5][CH:4]=1.O>C(N)=O>[Br:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:8]=1[C:9](=[O:14])[NH:10][CH:11]=[N:1]2
Reactant: O=c1[nH]c(=O)c2c(Br)cccc2o1
Reactant: N
Solvent: NC=O
Solvent: O
Product: O=c1[nH]cnc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1. Gaseous ammonia is introduced at 15° to 25° C. into a suspension of 43 g of 5-bromo-2H-1,3-benzoxazine-2,4(1H)-dione in 190 ml of formamide. A solution thereby results. The solution is stirred at room temperature for 3 h. and then the excess ammonia is driven off by passing nitrogen through the solution. The solution is then stirred at 15° C. for 15 h. The reaction solution is then cooled and treated with 250 ml of water while stirring. The crystals are filtered off, washed with water and dried in a vacuum. 26 g of 5-bromo-3H-quinazolin-4-one of m.p. 239°-240° C. are obtained.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCC(O)CC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Yield: 78.57 %

Procedure:
2α,3α-Epoxy-16β-(4-methyl-1-piperazinyl)-5α-androstane-17β-ol is reacted with 4-hydroxypiperidine as described in Example 3 to obtain the title compound in a yield of 78.57%, m.p.: 248°-250° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)C>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 65.2 %

Procedure:
To a mixture of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy -2-propylphenylthio)propoxy]-2-propylphenoxy]butyrate (2.1 g) in ethanol (10 ml) was added a solution of sodium hydroxide (0.26 g) dissolved into water (10 ml). After heating on a hot water bath for 5 minutes, the mixture was cooled by adding ice-water and was made acidic by addition of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The resultant residue was separated and purified by silica-gel column chromatography (eluting with ethanol:methylene chloride=3:100) to give the title compound (1.3 g, 65.2%) as colorless crystals, mp 79–81° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:25]([CH:32]1[CH2:37][N:36]([CH3:38])[CH2:35][CH:34]([C:39]([OH:41])=O)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[N:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([NH2:57])[CH:55]=3)[N:50]([C:58]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:25]([CH:32]1[CH2:37][N:36]([CH3:38])[CH2:35][CH:34]([C:39]([NH:57][C:54]2[CH:55]=[C:56]3[C:51](=[CH:52][CH:53]=2)[N:50]([C:58]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:49]=[C:48]3[C:45]2[CH:44]=[CH:43][N:42]=[CH:47][CH:46]=2)=[O:41])[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1CC(Cc2ccccc2)CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(Cc2ccccc2)CC(C(=O)Nc2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.11 mmol) was added to a suspension of 5-benzyl-1-methylpiperidine-3-carboxylic acid (0.1 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (0.1 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH:13]2[O:15][CH2:14]2)[NH:4][CH:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>O1CCOCC1>[C:16]([NH:20][CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([Cl:1])=[CH:3][NH:4]2)([CH3:19])([CH3:18])[CH3:17]
Reactant: Clc1c[nH]c2cccc(OCC3CO3)c12
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: CC(C)(C)NCC(O)COc1cccc2[nH]cc(Cl)c12

Procedure:
A solution of 1.13 g of 3-chloro-4-(2,3-epoxypropoxy)indole (prepared in manner analogous to the preparation of the starting material in Example 1, m.p. 107°-110°) and 2.2 g tert.butylamine in 15 ml of dioxan are boiled under reflux for 5 hours, evaporated to dryness and the title compound recrystallised from ether/petroleum ether. M.p. 95°-97°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[CH:8]=1>[I-].[K+].O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[NH:12][C:11](=[O:13])[NH:10][C:9](=[O:14])[CH:8]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: CNCCO
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CN(CCO)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a microwave reaction tube 2-(methylamino)ethanol (1.652 g, 22 mmol), 6-chloropyrimidine-2,4(1H,3H)-dione (1.465 g, 10 mmol), potassium iodide (KI) (0.017 g, 0.1 mmol) and water (20 mL) were added. The mixture was heated to 120° C. by microwave (Biotage Initiator) and stirred for 2 h. Then the solution was concentrated in vacuo to remove all the water. EtOH (10 mL) was added to the resultant residue. The suspension was filtered and the filter cake was collected to afford the title compound as a light-yellow solid (1.390 g, 75% yield),
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]#[N:17].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O>>[C:16]([CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:2]([CH3:1])[C:23](=[O:25])[C:22]1[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=1)#[N:17]
Reactant: CNc1cnccc1-c1ccccc1CC#N
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1CC#N

Procedure:
The title compound was prepared in analogy to example 90, from [2-(3-methylamino-pyridin-4-yl)-phenyl]-acetonitrile and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 5 days. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50) followed by a second chromatography, using preparative HPLC (Phenomenex Gemini® column, gradient of methanol:water (10:90 to 95:5)). Colorless solid (3%). MS (ESI): m/z=464.118 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[CH:16]1([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([N:4]4[C:5]5[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=5[C:2]([CH3:1])=[CH:3]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:18][CH2:17]1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Fc1ccc2c(NC3CC3)ncnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3c(NC4CC4)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Yield: 55.5 %

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.177 g, 1 mmol), sodium hydride (60% in oil, 40 mg, 1 mmol), Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine (0.20 g, 1 mmol), and N,N-dimethylformamide are sealed in a microwave vessel and irradiated at 100 degrees Celsius for 1500 seconds. The mixture is extracted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, filtered concentrated, and chromatographed to afford 0.2 g of 1-(4-Cyclopropylamino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one as a solid (55%). LC/MS m/z=361 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:7](=[N:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCCN
Product: CCCCCN=Cc1ccccc1

Procedure:
condensing N-pentylamine with benzaldehyde to produce the N-benzylidene-N-pentylamine of formula II
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:13][C:6]2=[N:7][CH:8]=[C:9]([CH:11]=O)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:14])[O:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=[C:5]2[CH:4]=[CH:3]1
Reactant: Nc1ccccc1
Reactant: CC1(C)C=Cc2cc(C=O)cnc2O1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C=Cc2cc(CNc3ccccc3)cnc2O1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 2,2-dimethyl-2H-pyrano[2,3-b]pyridine-6-carbaldehyde 18 (20 mg, 0.106 mg) in methanol (1 ml) was added aniline (0.01 mL, 0.12 mmol), NaCNBH3 (13 mg, 0.212 mmol) and ZnCl2 (29 mg, 0.212 mmol). The reaction was stirred for 30 minutes after which the solvent was removed by rotary evaporation and the 1M NaOH added to the residue, extracted with DCM, dried over MgSO4 and concentrated in vacuo. Purified by column chromatography (3:1 Hx/EtOAc) to give a white solid 20 mg (72%). 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.29 (s, 1H), 7.26-7.16 (m, 2H), 6.74 (t, J=7.2 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.26 (d, J=9.6 Hz, 1H), 5.67 (d, J=9.6 Hz, 1H), 4.21 (s, 2H), 1.51 ppm (s, 6H). 13C NMR (CDCl3) δ 159.6, 147.8, 146.4, 133.8, 132.2, 129.3, 128.4, 120.9, 118.0, 115.4, 113.0, 79.2, 45.4, 28.8 ppm. HRMS (ESI) m/z calcd for C11H11NO2 [(M+H)+] 190.0868. found: 190.0870.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1>C(Cl)Cl>[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A solution of triphenylphosphine (154 mg, 0.59 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (104 mg, 0.59 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 72, 200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (203 mg, 1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford the 2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-propionamide (164 mg, 58%) as a white foam: mp 83-86° C. (foam to gel); FAB-HRMS m/e calcd for C20H22Br2N2O3S (M+H)+ 528.9796, found 528.9783.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C@@H:14]([CH2:15][O:16][C:17](=[S:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][C:11]1=[O:28].P([O-])([O-])([O-])=O>CC#N>[O:28]=[C:11]1[CH2:12][CH2:13][C@H:14]([CH2:15][O:16][C:17](=[S:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:10]1[CH2:9][C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2]
Reactant: COC(=O)CCCC#CCN1C(=O)CC[C@@H]1COC(=S)NCCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(O)CCCC#CCN1C(=O)CC[C@@H]1COC(=S)NCCc1ccccc1
Yield: 53 %

Procedure:
Rabbit liver esterase (134 units/mg, 1 mg), ester 5 (6.0 mg, 0.015 mmol), MeCN (0.1 mL) and pH 7.2 phosphate buffer (2.0 mL) were stirred together at rt overnight. MeCN (5.0 mL) was added and the reaction was concentrated in vacuo. Purification of the residue by flash column chromatography on silica (100% CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 3.2 mg (55%) of the title compound (6).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[O:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH:15]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:11][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of succinic anhydride (20 g.) and phenoxycyclohexane (35.1 g.) in 1,2-dichloroethane (250 ml.) was stirred at 0° C and treated with powdered anhydrous aluminium chloride (58.2 g.) and stirring was continued for 5 hours at 0°-5° C. It was then poured carefully with stirring into ice-water (1 liter) containing concentrated hydrochloric acid (100 ml.). The organic layer was separated, washed with water and extracted with a solution of sodium hydroxide (8 g.) in water (250 ml.). The alkaline extract was adjusted to pH 4-6 by the addition of dilute hydrochloric acid to yield the product (6.8 g.), m.p. 190°-192° C after crystallisation from aqueous methanol.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Reactant: C1CCNCC1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCCCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and piperidine are converted to the named compound
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[N:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[N:26]=[CH:27][C:22]([Cl:21])=[CH:23][N:24]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(Cl)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-chloro-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=428.2 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1CCCCC1.ClC(Cl)(Cl)C(=N)O[C:34]([CH3:37])([CH3:36])[CH3:35].B(F)(F)F.CCOCC>ClCCl>[C:1]([NH:11][C@H:12]([C:21]([O:23][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](CCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
At room temperature, to a solution of (N-carbobenzyloxy)-(L)-homophenylalanine (0.476 g, 1.52 mmol) in anhydrous dichloromethane (3.5 mL) was added anhydrous cyclohexane (7 mL). To this clear solution was added with vigourous stirring tert-butyl 2,2,2-trichloroacetimidate (0.30 mL, 1.67 mmol) followed by dropwise addition of boron trifluoride diethyl etherate (30 mL). After stirring at room temperature for 2 hr, additional tert-butyl 2,2,2-trichloroacetimidate (0.45 mL, 2.50 mmol) and boron trifluoride diethyl etherate (45 mL) were added to the reaction mixture and stirring was continued overnight at room temperature. The reaction mixture was filtered through a pad of celite, and the residue was washed with ether. The solvent was removed from the filtrate by rotoevaporation and the crude product was purified by flash column chromatography on silica gel eluted with 2-6% ethyl acetate in hexane to afford the title compound (211 mg, 38% yield), homogeneous by TLC (4/1 hexane/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>C(Cl)Cl>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: CC(C)(O)C#N
Reactant: NCCCCO
Solvent: ClCCl
Product: CC(C)(C#N)NCCCCO
Temperature: 20 °C
Reaction time: 16 h

Procedure:
220 μl of acetone cyanohydrin and 200 μl of 4-amino 1-butanol were mixed together with stirring for 16 hours at 20° C. and then was diluted with 2 ml of methylene chloride, dried, filtered and the filtrate was concentrated under reduced pressure to obtain the propanonitrile which was used as is for the following stage.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6].[Cl:12][C:13]1[C:14](=[O:29])[N:15]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16]([CH3:20])=[CH:17][C:18]=1[OH:19].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C.C1OCCOCCOCCOCCOCCOC1>[Cl:12][C:13]1[C:14](=[O:29])[N:15]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:16]([CH3:20])=[CH:17][C:18]=1[O:19][CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: Cc1cc(O)c(Cl)c(=O)n1-c1c(F)cccc1F
Reactant: N#Cc1cc(F)ccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCc2ccc(F)cc2C#N)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 110.7 %

Procedure:
2-(bromomethyl)-5-fluorobenzonitrile (3.47 g, 16.2 mmol), 3-chloro-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (3.15 g, 11.6 mmol), K2CO3 (2.56 g, 18.6 mmol), and 18-crown-6 (0.15 g) were dissolved in N,N-dimethylacetamide (25 mL). Reaction mixture stirred on 60° C. oil bath for 4 hours. Solvent removed by distillation. Reaction neutralized with 5% citric acid. The solid product was washed with hexane followed by 30% EtOAc/hexane. Filtered a brown solid (5.2 g, 79% yield).