Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10]([C@@H:12]3[CH2:17][C@H:16]([NH:18]C(=O)OCC4C=CC=CC=4)[C@@H:15]([C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:14][CH2:13]3)[CH2:9][C:7]=2[N:8]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[N:4]=[CH:5][C:6]2[C:7](=[CH:9][N:10]([C@@H:12]3[CH2:17][C@H:16]([NH2:18])[C@@H:15]([C:29]4[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=4[F:37])[CH2:14][CH2:13]3)[CH:11]=2)[N:8]=1
Reactant: O=C(N[C@H]1C[C@@H](N2Cc3cnc(C(F)(F)F)nc3C2)CC[C@@H]1c1cc(F)c(F)cc1F)OCc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: N[C@H]1C[C@@H](n2cc3cnc(C(F)(F)F)nc3c2)CC[C@@H]1c1cc(F)c(F)cc1F

Procedure:
A solution of benzyl [(1S,2R,5S)-5-[2-(trifluoromethyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-(2,4,5-trifluorophenyl)cyclohexyl]carbamate (265 mg) and DDQ (111 mg) in 4 nm of dioxane was stirred for 4 h and the resulting product purified by chromatography on a Biotage Horizon® system (silica, gradient 10-35% ethyl acetate/dichloromethane) to give the title compound. LC-MS 549.3 (M+1). A portion of this product (20 mg) was dissolved in acetonitrile (2 mL), treated with trimethylsilyl iodide (0.2 mL), stirred for 30 min, and quenched with methanol (2 mL). The desired product was purified by preparative TLC (silica, 1:9:90 ammonium hydroxide:methanol:dichloromethane). LC-MS 415.3.
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=[C:48]([O:50]C)C(OC)=C(OC)C=2)=NC=1)C.COC1C=CC=CC=1C(Cl)=O.C(N(CC)CC)C>O1CCCC1>[CH3:48][O:50][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Agent: COc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)NC(C)c1cnc(Nc2cc(OC)c(OC)c(OC)c2)nn1

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (95 mg, 0.31 mmol), 2-methoxybenzoyl chloride (56 mg, 0.33 mmol), and triethylamine (0.050 mL, 0.36 mmol) in tetrahydrofuran (1 mL) gave 2-methoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (37 mg) as an off yellow solid. MS m/z 439 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH2:21][C:22]=1[O:23][Si](C)(C)C.Cl.N>O1CCCC1>[CH3:17][C:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cccnc12
Reactant: CC1=C(O[Si](C)(C)C)CCC1=O
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(c2cccc3cccnc23)CCC1=O
Temperature: -80 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A mixture of 38.7 g (186 mmol) of 8-bromoquinoline and 250 ml of tetrahydrofuran was cooled to −80° C., and 74.4 ml of n-butyllithium (2.5 M in hexane, 186 mmol) were subsequently added while stirring. The mixture was stirred for a further 15 minutes and 49.9 g (186 mmol) of 2-methyl-3-(trimethylsilyloxy)cyclopent-2-enone were added while stirring. The mixture was allowed to warm to room temperature while stirring and stirring was continued for a further one hour. The reaction mixture was then hydrolyzed by means of a mixture of 40 g of ice and 30 ml of concentrated hydrochloric acid and the mixture obtained in this way was refluxed for 3 hours. The mixture was allowed to cool to room temperature while stirring and ammonia solution was added until a pH of 12 had been reached. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue obtained in this way was distilled at 119-139° C. and 2×10−2 mbar to give 31.1 g (139.3 mmol, 74.9%) of 2-methyl-3-(8-quinolyl)cyclopent-2-enone.
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:19]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[CH3:20].C(O)C>Cl.O>[CH2:19]([N:21]1[C:1]([C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:13][C:14](=[O:16])[N:24]([CH2:25][CH3:26])[C:22]1=[O:23])[CH3:20]
Reactant: CCNC(=O)NCC
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=O)n(CC)c1=O
Temperature: 120 °C
Yield: 26.5 %

Procedure:
To a mixture of ethyl veratroylacetate (10 g) and N,N'-diethylurea (5.06 g) were added conc. hydrochloric acid (1 drop) and ethanol (1 ml). The mixture was heated at 120° C. for 3.5 hours under reduced pressure. To the residue was added another conc. hydrochloric acid (2 drops) and the mixture was heated again at 120° C. for 4 hours under reduced pressure. To the reaction mixture was added water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of diisopropyl ether and ethyl acetate to give 1,3-diethyl-6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (3.20 g).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.[OH-].[Na+].[OH-].[Li+]>>[CH3:1][C:2]1([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4cc(C(=O)O)ccc43)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2H-1-benzofuran-6-carboxylate (290 mg, 0.77 mmol), sodium hydroxide (0.06 g, 1.54 mmol) and lithium hydroxide (0.06 g, 1.54 mmol) is stirred at room temperature for 24 h. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. 10 ml of water and 10 ml of ethyl acetate are added. The mixture is acidified with concentrated hydrochloric acid solution to pH 1. After separation of the phases by settling, the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is obtained by recrystallization from a heptane/ethyl ether mixture (3/1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH2:26]([S:30](Cl)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]>>[CH2:26]([S:30]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Product: CCCCS(=O)(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and 1-butanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.41 (1H, d), 8.00 (1H, d), 7.96 (1H, s), 7.86 (1H, dd), 5.36 (2H, s), 4.71 (1H, m), 3.63 (2H, m), 3.01 (4H, m), 2.2 (2H, m), 1.99 (2H, m), 1.64 (2H, m), 1.39 (2H, m), 0.89 (3H, t).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3Cl)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>ClCCCl.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>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[CH:30]=[CH2:31])[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1ncnc2c1ncn2[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Yield: 67.2 %

Procedure:
To a solution of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-9H-purine (330 mg, 0.74 mmol) and tributyl(vinyl)stannane (0.26 mL, 0.88 mmol) in 1,2 dichloroethane (10 mL) was added Pd(Ph3P)2Cl2 (26 mg, 0.03 mmol) and the r×n mixture was heated at reflux overnight. The solvent was removed and the residue purified by flash chromatography (0 to 20% EtOAc/hexanes) to yield 215 mg (67%) of the title compound.
Reaction SMILES: C1COCC1.[CH3:6][NH2:7].[CH3:8][C:9]([Si:12]([CH3:47])([CH3:46])[O:13][C@H:14]([C@@H:19]([CH3:45])/[CH:20]=[C:21](/[CH3:44])\[CH2:22][C@H:23]([CH3:43])[C@@H:24]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C@H:25]([CH3:34])[C@@H:26]([OH:33])[C@@H:27]([CH3:32])/[CH:28]=[CH:29]\[CH:30]=[CH2:31])[C@@H:15]([CH3:18])[CH:16]=O)([CH3:11])[CH3:10]>CC(O)=O.CCOC(C)=O>[CH3:40][C:39]([Si:36]([CH3:38])([CH3:37])[O:35][C@H:24]([C@@H:23]([CH3:43])[CH2:22]/[C:21](/[CH3:44])=[CH:20]\[C@H:19]([CH3:45])[C@@H:14]([O:13][Si:12]([C:9]([CH3:8])([CH3:11])[CH3:10])([CH3:47])[CH3:46])[C@@H:15]([CH3:18])[CH2:16][NH:7][CH3:6])[C@H:25]([CH3:34])[C@@H:26]([OH:33])[C@@H:27]([CH3:32])/[CH:28]=[CH:29]\[CH:30]=[CH2:31])([CH3:41])[CH3:42]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CNC
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
To a stirred THF solution of methylamine (2 M, 1.01 mL, 4 eq, 2.02 mmol) is added THF (10 mL) solution of (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[(1,1-dimethylethyl) dimethylsilyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal (300 mg, 0.505 mmol, 1 eq) at 23° C. After stirring for 20 minutes, NaBHAc3 is added followed by addition of 1 drop of AcOH. The solution is stirred for an additional 2 hours and diluted with EtOAc (10 mL), washed with aqueous saturated Na2CO3 (2×5 mL), brine, dried with Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, gradient 10–30% MeOH/EtOAc) to give the desired compound (180 mg, 59%) as a colorless oil.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]([N:13]=[C:14]=[O:15])[CH:11]=[CH2:12]>>[CH2:10]([NH:13][C:14](=[O:15])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]#[N:9])[CH:11]=[CH2:12]
Reactant: C=CCN=C=O
Reactant: N#Cc1ccccc1N
Product: C=CCNC(=O)Nc1ccccc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.2 %

Procedure:
A mixture of anthranilonitrile (10.0 g, 85 mmol) and allyl isocyanate (7.5 mL, 85 mmol) was slightly heated to dissolve. The resulting solution was allowed to stir at room temperature for two days. The solid was collected by filtration and washed with ether (10 mL) to give 14.4 g (100%) of 2-(3-allylureido)benzonitrile. An analytical sample was recrystallized from ethanol. IR (KBr): 3331, 3263, 2226 (CN), 1639 cm-1. 1H NMR (300 MHz, DMSO-d6): δ3.74 (p, 2H, CH2), 5.09 (q, 1H, =CH), 5.17 (q, 1H, =CH), 5.86 (m, 1H, CH), 7.09 (t, 2H, Ar--H), 7.56 (t, 1H, Ar--H), 7.67 (d, 1H, Ar--H), 8.43 (d, 1H, Ar--H), 7.65 (d, 1H, NH), 8.54 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ41.47, 101.00, 114.97, 116.99, 120.61, 120.73, 122.22, 132.96, 133.83, 135.69, 142.66, 154.32. Anal. Calcd for C11H11N30 (201.23): C, 65.66; H, 5.51; N, 20.89. Found: C, 65.38; H, 5.51; N, 21.05.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:6]=[N:5]1.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([O:10][CH2:9][C:8]2[N:4]([CH3:3])[N:5]=[N:6][C:7]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:22][CH:23]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cn1nnc(-c2ccccn2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a suspension of sodium hydride (55%, 92 mg, 2.10 mmol) in THF (3 mL) was added a solution of (3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-methanol (400 mg, 2.103 mmol) in THF (5 mL) under ice cooling. The mixture was then allowed to warm up to room temperature and stirred for 30 min. Again under ice cooling was added a solution of 3,6-dichloropyridazine (315 mg, 2.10 mmol) in THF (5 mL) and the resulting mixture stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (630 mg, 99%) as a white solid. MS: m/e=303.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[CH:63]=[CH:62][C:61]([S:64](Cl)(=[O:66])=[O:65])=[C:60]([CH3:68])[CH:59]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:61]1[CH:62]=[CH:63][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[CH:59][C:60]=1[CH3:68])(=[O:66])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(NC(C)=O)cc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) was reacted with 4-acetylamino-2-methyl-benzenesulfonyl chloride to give (S)-2-({(S)-7-(4-acetylamino-2-methyl-benzenesulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. The title compound was prepared by the hydrolysis of (S)-2-({(S)-7-(4-acetylamino-4-methyl-benzenesulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (8 mg) according to General Procedure B. LCMS (m/z): 945.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].CN(C)C=O.[H-].[Na+]>O>[CH3:11][O:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:12][CH2:13][CH3:14])=[C:2]([CH:7]=1)[O:1][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CBr
Reactant: CCCc1ccc(OCOC)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc(OCOC)cc1OCC(=O)OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 78 %

Procedure:
To a mixture of 2-hydroxy-4-methoxymethoxy-1-propylbenzene (1.50 g), methyl bromoacetate (1.39 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 1.50 g) under ice-cooling. The reaction mixture was stirred at room temperature for 13 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-(5-methoxymethoxy-2-propylphenoxy)acetate as a colorless oil (1.60 g, 78%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:16](=[O:17])[CH:15]=[C:14](O)[C:13]([C:19]([NH2:21])=O)=[N:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:24])=O>CC#N>[Cl:24][C:14]1[C:13]([C:19]#[N:21])=[N:12][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16](=[O:17])[CH:15]=1
Reactant: COc1ccc(-n2nc(C(N)=O)c(O)cc2=O)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc(-n2nc(C#N)c(Cl)cc2=O)cc1OC
Reaction time: 19 h

Procedure:
The starting amide (30) (190 mg) was dissolved in 1 ml of CH3CN, treated with 1 ml of phosphorus oxychloride, and heated to reflux. After 18-20 hours the reaction was complete by HPLC. The reaction mixture was poured into ice and stirred for one hour. The product was extracted with ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. This material was then purified by normal phase column SiO2 chromatography affording 90 mg of desired nitrile chloride (31) as a solid. MS+: m/e=292.0 (M+H), 1H-NMR (500 MHz, MeOH-d4): d 7.40 (s, 1H), 7.18 (s, 1H), 7.12 (d, 1H), 7.08 (d, 1H), 3.90 (s, 3H), 3.85 (s, 3H), ppm.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][CH:12]=[O:13])[CH:7]=[CH:8][C:9]=1[F:10]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=CCc1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
NaBH4 (1.46 g, 0.038 mol) was added at 0° C. to a solution (3,4-difluoro-phenyl)-acetaldehyde (5.5 g 0.35 mol, from step (ii) above) in 90 ml ethanol and stirred at RT overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between 50 ml of 1 N HCl and 50 ml of diethylether. Organic layer was washed with water, dried over sodium sulfate and solvent evaporated under reduced pressure to give (5.5 g) of the sub-title compound as a liquid. This was directly taken for next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([S:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[C:5]([CH3:14])[N:4]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])([O-:17])=[O:16]>C(Cl)Cl>[CH3:13][O:12][CH2:11][CH2:10][S:9][C:7]1[CH:6]=[C:5]([CH3:14])[N:4]=[C:3]([N:2]([CH3:1])[C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])(=[O:26])=[O:25])=[O:29])[N:8]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CNc1nc(C)cc(SCCOC)n1
Solvent: ClCCl
Product: COCCSc1cc(C)nc(N(C)C(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1

Procedure:
By using the procedure of Equation 2 with an equivalent amount of appropriate 2-methylaminopyrimidines or 2-methylamino-1,3,5-triazines and appropriately substituted benzenesulfonylisocyanates or isothiocyanates, the compounds of Table 3 can be prepared. For example, to a dry stirred solution of 19.7 parts of 2-methylamino-4-(2-methoxyethylthio)-6-methylpyrimidine in 300 parts of methylene chloride at ambient temperature is added 22.8 parts of 2-nitrobenzenesulfonylisocyanate. That mixture is stirred and refluxed for 4 hours, and then the methylene chloride is removed under reduced pressure. The resulting solid is triturated with 1-chlorobutane to yield N-[N-[4-(2-methoxyethylthio)-6-methylpyrimidin-2-yl]-N-methylaminocarbonyl]-2-nitrobenzenesulfonamide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:22]1[CH2:27][CH:26]=[C:25]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:37][C:34]4[CH:35]=[C:36]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5[C:25]4[CH2:26][CH2:27][NH:22][CH2:23][CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc2[nH]cc(C3=CCNCC3)c2c1
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4[nH]cc(C5=CCNCC5)c4c3)ncc21

Procedure:
The title compound was prepared using Buchwald reaction from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.31 (m, 4H) 1.65 (m, 8H) 2.02 (m, 3H) 2.98 (br. s., 2H) 3.46 (s, 3H) 4.02-4.25 (m, 2H) 4.88 (br. s., 2H) 6.26 (s, 1H), 6.65 (d, J=8 Hz, 1H), 7.10 (s, 1H), 7.98 (s, 1H) 8.34 (d, J=8.0 Hz, 1H) 8.45 (s, 1H). [M+H] calc'd for C26H29F2N7O, 494. found 494.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[O:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](Cl)=[S:20])=[CH:14][CH:13]=1.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[O:9][N:8]([C:19]([O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)=[S:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1c[nH]oc1=O
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C(=S)Oc2ccccc2)oc1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5-Oxo-2,5-dihydro-isoxazole-4-carboxylic acid ethyl ester described in Preparation Example 112 (1.00 g, 5.17 mmol), phenyl chlorothionoformate (786 μl, 5.69 mmol) and pyridine (919 μl, 11.4 mmol) were dissolved at 0° C. in toluene (20 mL), and the solution was stirred at room temperature for 17 hours under nitrogen atmosphere. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (1.66 g, 5.66 mmol, quantitatively) was obtained as a pale yellow solid.