Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9].[I:39][CH3:40]>O1CCOCC1>[I-:39].[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[N+:14]([CH3:40])[CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:9]
Reactant: CI
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2cccnc2c(=O)n1C
Solvent: C1COCCO1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2ccc[n+](C)c2c(=O)n1C
Product: [I-]

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-fluorophenyl)-7,8-dihydro-N, 7-dimethyl-8-oxo-6pyrido[3,4-b]pyridinecarboxamide (Example 1) (175 mg), iodomethane (3 ml) and dioxane (3 ml) was heated for 16 hours under reflux. The solvent was distilled off to leave the above-titled compound as yellow crystals (200 mg), m.p.184°-185° C. (decomp.) (recrystallized from dioxane-ethyl acetate).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][NH2:10])=[N:6][N:5]=[N:4]1)[CH3:2].C(I)C.BrCC[CH2:17][OH:18]>>[NH2:10][CH2:9][CH2:8][C:7]1[N:3]([CH2:1][CH2:2][CH2:17][OH:18])[N:4]=[N:5][N:6]=1
Reactant: CCn1nnnc1CCN
Reactant: OCCCBr
Solvent: CCI
Product: NCCc1nnnn1CCCO

Procedure:
This material is prepared by an analogous procedure to intermediate CI2 by replacing the ethyliodide in step 1 with 3-bromo-1-propanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[C:27]([O-:30])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO.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>[C:23]([C:4]1[C:5]([O:21][CH3:22])=[C:6]([CH:20]=[C:2]([C:9]2[C:27](=[O:30])[NH:15][CH:12]=[CH:11][CH:10]=2)[CH:3]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 5—A mixture of 120 (0.20 g, 0.46 mmol), 112 (0.095 g, 0.69 mmol), Pd(PPh3)4 (0.053 g, 0.046 mmol) and Na2CO3 (0.15 g, 1.4 mmol) in DCM/MeOH (3:1, 8 mL) was irradiated in microwave synthesizer at 115° C. for 35 min. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH/NH4OH and the recovered product triturated with ether to afford I-71 as a solid.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: NC1CCc2ccccc21
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(NC1CCc2ccccc21)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 1-aminoindane as the starting materials.
Reaction SMILES: [Cl:1]C1C=C(NC(NC)=O)C=CC=1Cl.O=CC(Cl)(Cl)Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([N:31]([CH:33](O)[C:34]([Cl:37])([Cl:36])[Cl:35])[CH3:32])=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].S(Cl)(Cl)=O>S(=O)(=O)(O)O.C(OCC)C>[CH3:32][N:31]([CH:33]([Cl:1])[C:34]([Cl:37])([Cl:36])[Cl:35])[C:29]([NH:28][C:23]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=1)=[O:30]
Reactant: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(O)C(Cl)(Cl)Cl
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Agent: O=CC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(Cl)C(Cl)(Cl)Cl
Temperature: 65 °C

Procedure:
1-(3,4-dichlorophenyl)-3-methyl urea (15.2 g, 0.07 mol) was combined with 15.0 g (0.1 mol) of chloral and 5 drops of concentrated sulfuric acid. The mixture was heated for an hour to effect reaction, then stripped under vacuum. To the crude 1-(3,4-dichlorophenyl)-3-(1-hydroxy-2,2,2-trichloroethyl)-3-methyl urea was added an excess of thionyl chloride and the mixture was heated gradually to a maximum of 65° C. Diethyl ether was added to the crude product, and the insoluble product was collected on a filter, washed twice with diethyl ether and dried. The 15.3 g of product, which melted at 132°-140° C., analyzed as follows: %Cl, calculated 55.2, found 46.0. The product is the seventh compound tabulated in Table I.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)#[CH:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:42][CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52](=[O:64])[C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=2[C:60]([F:63])([F:62])[F:61])[CH2:48][CH2:47]1)=[O:45]>CN(C=O)C.O>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:42][CH2:43][C:44]([N:46]2[CH2:47][CH2:48][N:49]([C:52](=[O:64])[C:53]3[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=3[C:60]([F:62])([F:61])[F:63])[CH2:50][CH2:51]2)=[O:45])=[O:18])=[CH:19][CH:20]=1)#[CH:11]
Reactant: C#Cc1ccc(C(=O)O)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 41.4 %

Procedure:
DIPEA (263.67 mg, 0.34 mL, 2.04 mmol) was added to a stirred solution of 4-Ethynyl-benzoic acid (100 mg, 0.68 mmol) in DMF (1.5 mL). HOBT (92 mg, 0.68 mmol) and EDCI (156.42 mg, 0.81 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (253 mg, 0.68 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with 5% sodium bicarbonate solution followed by brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was recrystallized from a mixture of EtOAc and ether to afford 130 mg (41.1% yield) of 4-Ethynyl-N-{2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide. LCMS Purity: 87.29%. 1H NMR (DMSO-d6): δ 8.7 (m, 1H), 8.0-7.8 (m, 3H), 7.6-7.4 (m, 4H), 4.4 (s, 1H), 4.2-4.1 (m, 2H), 3.8-3.4 (m, 3H), 3.2-3.0 (m, 2H).
Reaction SMILES: [Br:1][C:2]([F:11])([F:10])[CH2:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[CH2:12]=[O:13]>C[Si](Cl)(C)C>[Br:1][C:2]([F:10])([F:11])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:12][OH:13])[C:6](=[O:9])[CH2:5]1
Reactant: O=C1CC(CC(F)(F)Br)CN1
Reactant: C=O
Agent: C[Si](C)(C)Cl
Product: O=C1CC(CC(F)(F)Br)CN1CO
Yield: 93 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of 4-(2-bromo-2,2-difluoro-ethyl)-pyrrolidin-2-one a6 (0.46 g, 2 mmol), paraformaldehyde (0.12 g) and TMSCl (10 ml) is heated at 60° C. for 1 h. The reaction mixture is evaporated to give the crude 4-(2-bromo-2,2-difluoro-ethyl)-1-hydroxymethyl-pyrrolidin-2-one a7 (0.48 g, 92%).
Reaction SMILES: [C:1]([C:5]1[Se:13][C:12]2[C:11](=[O:14])[NH:10][N:9]=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].IC.[I-].[K+]>CC(C)=O>[C:1]([C:5]1[Se:13][C:12]2[C:11](=[O:14])[N:10]([CH3:15])[N:9]=[N:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc2nn[nH]c(=O)c2[se]1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nnc2cc(C(C)(C)C)[se]c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 6-(tert-butyl)-3H-selenopheno[3,2-d]1,2,3-triazin-4-one (2.0 g, 7.78 mmol) in acetone (70 mL) was added sequentially potassium carbonate (2.14 g, 15.56 mmol), iodomethane (0.58 mL, 9.3 mmol) and potassium iodide (catalytic) at rt and the mixture was stirred at rt for 16 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure and the residue was chromatographed over silica gel column using chloroform-methanol (95:05) as eluents to give the product as a off-white color solid (1.0 g, 47%), which was recrystallized from chloroform-methanol (700 mg, 34%), mp 98-100° C. IR (neat) νmax 2961, 1679, 1242, 1220, 1001, 969 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.58 (1H, s, H-7), 4.04 (3H, s, —NCH3), 1.48 (9H, s, tert-butyl); 13C NMR (100 MHz, CDCl3): δ 176.0, 157.5, 154.7, 128.8, 121.5, 37.5, 37.3, 32.5; LC-MS (positive ion mode): m/z 292, 294 (M+Na)+.
Reaction SMILES: C1(=[N:7]O)CCCCC1.[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].OS(O)(=O)=O.O=S(=O)=O.S(O)(O)(=O)=O.[C:28]1(=[O:35])[NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH3:36]>>[C:28]1(=[O:35])[NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[S:9]([O-:13])([O-:12])(=[O:11])=[O:10].[NH4+:7].[NH4+:36]
Reactant: ON=C1CCCCC1
Reactant: N
Reactant: O=S(=O)(O)O
Agent: O=C1CCCCCN1
Agent: O=S(=O)=O
Product: O=S(=O)([O-])[O-]
Product: [NH4+]

Procedure:
The Beckmann rearrangement of the cyclohexanone oxime is carried out with sulfuric acid or oleum. The caprolactam sulfate prepared in this case and excess sulfuric acid are reacted with ammonia to give caprolactam and ammonium sulfate.
Reaction SMILES: O=C[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)O.C1C=[N+]([C@@H]2[O:23][C@H:22](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H:21](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl-].[K+].[C:63](#N)[CH3:64]>C1(C)C=CC=CC=1>[CH2:22]([O:23][C:7]1([O:8][CH2:63][CH3:64])[CH2:5][CH2:3][O:12][CH2:11][C@@H:9]1[OH:10])[CH3:21]
Reactant: CC#N
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC1(OCC)CCOC[C@@H]1O
Temperature: 30 °C
Reaction time: 17 h

Procedure:
The above organic solution of 4,4-dimethoxydihydro-2H-pyran-3(4H)-one was extracted 3× with phosphate buffered water (0.55 L). To the combined aqueous extracts was added D-glucose (180 g, 100 mmol), and the solution was heated to 30° C. When the solution exceeded 27° C. upon heating B-NADP+ (1.60 g, 499 mmol), GDH-103 (1.60 g, 499 mmol), and KRED-130 (1.60 g, 499 mmol) were added and the mixture was stirred for 17 h at 30° C. Potassium chloride (200 g, 2.68 mol) and acetonitrile (1.3 L) were added. After 30 min, the reaction mixture was transferred to 6 L sep funnel and additional MeCN (0.67 L) and toluene (0.87 L) were added. The aqueous layer was back extracted 1× with a mixture of acetonitrile (1.95 L) and toluene (0.65 L), and 1× with acetonitrile (1.5 L). The combined organic extracts were concentrated in vacuo to provide (3S)-4,4-diethoxytetrahydro-2H-pyran-3-ol.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=2[F:24])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:3][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:25])[S:11]([C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CN(C)c1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C)c1ccc(N(C)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg, 0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system was added under N2 at room temperature a 1M solution of lithium bis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirred for 10 min followed by addition of MeI (65 mg, 0.028 mL). The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the crude product purified by HPLC using silica as the stationary phase and eluting with 20%EtOAc/Hex (v/v) to afford the product as a white solid in 60% yield (62 mg). EI m/z: 380(35, M+), 149(100). 1H NMR (CD3OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H), 3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C15H13F5SO2N2: C, 47.37; H 3.45; N 7.37. Found: C, 47.37; H, 3.49; N, 7.32.
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][CH:9]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])#[N:2].[CH3:18][CH:19]([CH3:42])[CH:20]([NH:25][C:26]([C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)=[CH:31][N:32]=1)=[O:27])[C:21]([O:23][CH3:24])=[O:22]>>[C:1]([C:3]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:30]3[S:29][C:28]([C:26]([NH:25][CH:20]([CH:19]([CH3:42])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])=[O:27])=[N:32][CH:31]=3)=[CH:34][CH:35]=2)=[O:14])=[CH:16][CH:17]=1)([CH2:4][CH3:5])[CH2:6][CH3:7])#[N:2]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: CCC(C#N)(CC)c1ccc(C(=O)OC)cc1
Product: CCC(C#N)(CC)c1ccc(C(=O)Nc2ccc(-c3cnc(C(=O)NC(C(=O)OC)C(C)C)s3)cc2)cc1

Procedure:
The title compound was synthesized analogous to Example 85, using methyl 4-(3-cyanopentan-3-yl)benzoate (Intermediate 6) and intermediate 2. 1HNMR (DMSO-d6, 300 MHz) δ 10.52 (s, 1H), 8.78 (d, 1H), 8.41 (s, 1H), 8.03 (d, 2H), 7.93 (d, 2H), 7.81 (d, 2H), 7.62 (d, 2H), 4.33 (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 2.1-2.02 (m, 4H), 0.95 (t, 6H), 0.81 (t, 6H); MS (ES+): m/z 533.2 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]=[C:2]1[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][N:18]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:16]=[C:11]12.IC1C=CC=C2C=1CCN1C(=O)CN=C(C3C=CC=C(OC)C=3)C=C12.C([Sn](CCCC)(CCCC)C1OCCC=1)CCC>O1CCOCC1.CCOC(C)=O.CCCCCCC.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>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:17]2[CH:16]=[C:11]3[C:12]4[C:7]([CH2:8][CH2:9][N:10]3[C:20](=[O:21])[CH2:19][N:18]=2)=[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:15]=[CH:14][CH:13]=4)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C2=NCC(=O)N3CCc4c(C5=CCCO5)cccc4C3=C2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: COc1cccc(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)c1
Solvent: CCCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C2=NCC(=O)N3CCc4c(cccc4C4CCCO4)C3=C2)c1
Temperature: 150 °C

Procedure:
9-(4,5-dihydrofuran-2-yl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 57-1. A mixture of 9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 30) (1.0 g, 2.25 mmol), tributyl(4,5-dihydrofuran-2-yl)stannane (1.21 g, 3.38 mmol) and Pd(PPh3)4 (0.13 g, 0.11 mmol) in 1,4-dioxane (10 mL) was heated in a microwave reactor at 150° C. for 90 min. The mixture was then diluted with AcOEt and filtered. The filtrate was concentrated in vacuo and the crude product obtained was purified by flash chromatography (SiO2, heptane to heptane/AcOEt 1:1) to give a brown solid, which was suspended in heptane and heated to reflux. The suspension was then allowed to cool to RT and then filtered. The filter cake was then dried in vacuo to afford the title compound (543 mg) as a beige solid. UPLC-MS: MS 387.2 (M+H+); UPLC rt 1.10 min.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[C:6](=[S:21])[O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3.[CH3:22]C(C)=O.C[I:27]>>[I-:27].[OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N+:7]2=[C:6]([S:21][CH3:22])[O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3
Reactant: CI
Reactant: CC(C)=O
Reactant: COc1cc2c(cc1OC)C1C(CO)COC(=S)N1CC2
Product: COc1cc2c(cc1OC)C1C(CO)COC(SC)=[N+]1CC2
Product: [I-]
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 3.09 g (0.01 mole) of 1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3-a]isoquinoline-4-thione in acetone 1.94 g (0.02 mole) of methyl iodide are added. The reaction mixture is allowed to stand at room temperature for 24 hours. The crystalline product is filtered off, washed and recrystallized from a mixture of acetone and ether. Yield: 70% (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.[C:28]([O-:31])([O-])=[O:29].[Na+].[Na+].[C:34](#[N:36])[CH3:35]>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>[NH2:36][C@@H:34]([CH2:35][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=2)=[CH:16][CH:15]=1)[C:28]([OH:31])=[O:29]
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Nc1nc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (0.75 g, 1.89 mmol), L-p-boronophenylalanine (0.47 g, 2.26 mmol), Pd(PPh3)2Cl2 (79 mgs, 0.113 mmol), Na2CO3 (0.44 g, 4.15 mmol), acetonitrile (10 mls), and H2O (10 mls) were combined in a 20 ml microwave reactor and heated in the microwave at 150° C. for 7 minutes. The reaction was complete by LCMS (Sunfire, neutral). The mixture was concentrated, dissolved in NaOH (20 m is 0.5 N), filtered, extracted with ether three times, and cooled to 0° C. At 0° C., 1.0 N HCl was added slowly until a pH of 6.5 was attained. The mixture was stirred at 0° C. for 30 minutes and the product was filtered, dried in air, treated with excess 2.0 N HCl in ether, concentrated, then triturated with CH2Cl2 to give 1.12 g, 99% (95.5% purity). 385 mgs were purified via prep HPLC (Sunfire, TFA), concentrated, treated with excess 1.0 N HCl (aq.), concentrated to a small volume and lyophilized to afford 240 mgs of the captioned compound. M+1=527; 1H NMR 6 (CD3OD) 7.86 (d, 2H), 7.64 (s, 4H), 7.49 (d, 2H), 7.36 (m, 2H), 7.28 (m, 1H), 7.02 (m, 1H), 6.95 (s, 1H), 6.75 (q, 1H), 4.26 (t, 1H), 3.32 (m, 1H), 3.21 (m, 1H).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH3:17])[C@:10]([CH3:16])([OH:15])[C:11]([F:14])([F:13])[F:12])C1C=CC=CC=1.O>CO>[NH2:8][C@H:9]([CH3:17])[C@:10]([CH3:16])([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: C[C@@H](N(Cc1ccccc1)Cc1ccccc1)[C@](C)(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: C[C@@H](N)[C@](C)(O)C(F)(F)F
Reaction time: 8 h
Yield: 80.4 %

Procedure:
(2S,3R)-3-(Dibenzylamino)-1,1,1-trifluoro-2-methylbutan-2-ol (Example 52B) (1.94 g, 5.75 mmol) was dissolved in MeOH (50 mL) and an then treated with the catalyst (0.612 g, 10% dry weight, 50% water). The reaction vessel was then purged with alternating vacuum and N2 (7×). H2 was introduced and then the vessel was purged again with vacuum alternated with H2 (3×). The reaction vessel was then finally charged with H2 (90 psi). The pressure was allowed to drop to ca. 80 psi and allowed to stay there overnight (H2 uptake appeared to stop). After 15 h, the reaction was purged with N2/vacuum cycles and the catalyst/carbon was removed by filtration through celite. The celite cake was rinsed with MeOH and the resulting filtrate was carefully concentrated to a white solid by rotavap followed by finishing the last part of the liquid volume with an N2 blow down. The resulting grey solid/film was dissolved in CH2Cl2 and then filtered through a microfilter to remove remaining Pd/C. The resulting pale yellow filtrate was then blown down and exposed to light vacuum to afford a pale yellow solid (0.726 g, 80%) PMR of this material showed excellent purity and no remaining sm: 1H NMR (400 MHz, DMSO-d6) δ 2.95 (q, J=6.7 Hz, 1H), 1.60 (bs, 2H), 1.13-1.11 (m, 3H), 0.96-0.94 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][N:13]1[C:17]([NH2:18])=[N:16][N:15]=[N:14]1.N1C=CC=CC=1.O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:17]1[N:13]([CH3:12])[N:14]=[N:15][N:16]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cn1nnnc1N
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: Cn1nnnc1NC(=O)c1ccc(Cl)cc1Cl

Procedure:
In a microwave oven, 209 mg (1.0 mmol) of 2,4-dichlorobenzoyl chloride, 198 mg (2.0 mmol) of 1-methyl-5-aminotetrazole and 237 mg (3 mmol) of pyridine in 3 ml of acetonitrile are stirred at 130° C. for 45 min. Water is then added, and the product is filtered off with suction and washed with ether. Yield 80 mg (30%).
Reaction SMILES: [C:1]1([P:7](Cl)(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1[CH2:15]OCC1.[CH:16]([Mg]Br)=[CH2:17].Cl>CCOCC>[C:1]1([P:7](=[O:8])([CH:16]=[CH2:17])[CH:11]=[CH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C[Mg]Br
Reactant: C1CCOC1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: C=CP(=O)(C=C)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Phenylphosphonic dichloride (2.00 g, 10.26 mmol) was taken up in 1:1 THF:Et2O (100 mL) and cooled to −78° C. Vinylmagnesium bromide (21.54 mL, 21.54 mmol, 1.0 M in THF) was added dropwise. After stirring for 2 h at −78° C., the cold reaction was poured into 2 N HCl, and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to a yellow oil. Flash chromatography (0-10% MeOH/EtOAc) afforded phenyl(divinyl)phosphine oxide as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.72-7.67 (m, 2H), 7.54-7.50 (m, 1H), 7.49-7.45 (m, 2H), 6.44 (ddd, J=24.5, 18.7, 12.4 Hz, 2H), 6.29-6.18 (m, 4H). MS: cal'd 179 (MH+), exp 179 (MH+).
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7]1>CO>[CH3:1][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: O=C(O)CCCC1CCNCC1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
Trimethylsilyl chloride (9.2 ml, 72.46 mmol) was added to a solution of 4-piperidin-4-yl-butyric acid (1) (5.00 g, 24.15 mmol) dissolved in anhydrous methanol (100 mL). The resulting solution was stirred at room temperature for 48 hours, and concentrated under vacuum to complete dryness to give 2 (4.50 g, 97%) as a white solid, which was used directly in the next step without further purification: 1H NMR (300 MHz, CD3OD) δ 1.20-1.46 (m, 4H), 1.52-1.74 (m, 3H), 1.96 (d, 2H), 2.35 (t, 2H), 2.96 (t, 2H), 3.36 (t, 2H), 3.68 (s, 3H); ESI MS m/z 186 [C10H19NO2+H]+.