Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:18][S:17](=[O:20])(=[O:19])[CH2:16][C@H:15]3[NH2:21])[CH2:8]2)=[CH:4][CH:3]=1.[ClH:24].[N+](C1C=CC([O:34][C:35](=O)[NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=CC=1)([O-])=O.C(N(CC)CC)C>CN(C)C=O>[ClH:24].[ClH:24].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:18][S:17](=[O:19])(=[O:20])[CH2:16][C@H:15]3[NH:21][C:35]([NH:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:34])[CH2:8]2)=[CH:22][CH:23]=1
Reactant: O=C(NCCN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 67 h
Yield: 149.9 %

Procedure:
(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-1,1-dioxo-tetrahydrothiophen-3-ylamine (47 mg, 137 μmol) and (2-morpholin-4-yl-ethyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (55 mg, 164 μmol) were dissolved in N,N-dimethylformamide (1 mL) and treated with triethylamine (23 μL, 164 μmol). The mixture was stirred at room temperature for 67 h , and then concentrated. The residue was purified by flash column chromatography (3% methanol/dichloromethane containing 0.3% aqueous ammonium hydroxide). After isolation, the product was dissolved in 1N hydrochloric acid and water and lyophilized to provide a fluffy white solid (70 mg, 90%). 1H NMR (300 mHz, CD3OD) δ7.15 (m, 2H), 6.98 (m, 2H), 4.21 (q, J=8.1 Hz, 1H), 3.68 (m, 4H), 3.49 (dd, J=13.6, 8.1 Hz, 1H), 3.35 (m, 1H), 3.25 (t, J=6.6 Hz, 2H), 2.98 (m, 2H), 2.78 (m, 2H), 2.6-2.4 (11H), 2.07 (m, 1H), 1.9-1.5 (5H), 0.98 (m, 1H), ESI MS: (M+H)+=497.1.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.Cl.[C]=O.[CH:22]([OH:24])=[O:23]>>[C:22]([OH:24])(=[O:23])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [C]=O
Product: O=C(O)C=Cc1ccccc1
Yield: 86.9 %

Procedure:
A mixture of 103.2 g of 1,1,1,3-tetrachloro-3-phenylpropane, 114 g of 85% formic acid and 4.2 g of 93% sulphuric acid is refluxed under stirring at a temperature in the range 100° to 110° C. for 6 h with evolution of hydrogen chloride and carbon monoxide. The reaction mixture is cooled, the crystals so precipitated are filtered off and washed with water to give 51.5 g of cinnamic acid in total yield of 98 per cent (melting point 127° to 133° C., min. 98% purity).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](F)[CH:22]=1>>[Br:20][C:21]1[CH:22]=[C:23]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)[CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cccc(Br)c1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2cccc(Br)c2)c1

Procedure:
In analogy to example 4.6, Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine and 1-bromo-3-fluoro-benzene were converted to yield {4-[1-(3-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[F:10][C:11]1[CH:12]=[N:13][C:14](=[O:17])[NH:15][CH:16]=1>CN(C)C=O>[CH2:1]([N:15]1[CH:16]=[C:11]([F:10])[CH:12]=[N:13][C:14]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ncc(F)c[nH]1
Reactant: ClCc1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=c1ncc(F)cn1Cc1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
Benzyl chloride (0.01 mol) was added to a stirred mixture of the potassium salt of 5-fluoropyrimid-2-one (0.007 mol) in dimethylformamide (40 ml) and the mixture stirred at room temperature until chromatography showed the reaction to be complete. The solvent was then evaporated at reduced presure (1 mm Hg) and the residue was extracted with chloroform (100 ml). The chloroform solution was washed with aqueous 2 N NaCH (2×3 ml) and with water (3 ml) before drying (MgSO4) and evaporation; yield 50%, m.p. 163° C. (ethyl actate). (Found: C, 64.69; H, 4.49. Calc. for C11H9FN2O: C, 64.70; H, 4.44).
Reaction SMILES: FC(F)(F)C(O)=O.C(O)(=O)C.Br[CH:13]([C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16].[C:39]([O-:42])(=[S:41])[CH3:40].[Na+]>C(#N)C>[C:39]([S:41][CH:13]([C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])(=[O:42])[CH3:40]
Reactant: CC([O-])=S
Reactant: O=C(c1ccccc1)C(Br)C(C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC(C(=O)c1ccccc1)C(C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1

Procedure:
A 0.01 mole sample of 3-benzoyl-2-(phenyl)propionic acid is dissolved in tetrahydrofuran and 0.01 mole of N,N-carbonyldiimidazole added. After stirring 3 hours at room temperature, 0.01 mole of L-proline t-butyl ester is added. After 24 hours the solvent is removed and 1-[3-benzoyl-2-(phenyl)-propionyl]-L-proline t-butyl ester isolated. The preceding compound is reacted with trifluoroacetic acid to remove the t-butyl group. Separation of isomers A and B is carried out as described for Example 69. Reaction of the isomers with bromine is acetic acid and reaction of the 1-[3-bromo-3-benzoyl-2-(phenyl)propionyl]-L-proline isomers with sodium thioacetate in acetonitrile as for Example 69 gives the products of the example. The product from isomer A is separated by chromatography to give [S-(R*,R*)] and [S-(R*,S*)]-1-[3-acetylthio-3-benzoyl-2-(phenyl)propionyl]-L-proline.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)[CH2:6]1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31].O.C(OCC)(=O)C>N1C=CC=CC=1>[S:30]([O:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)[CH2:6]1)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: C[C@]12CC[C@H](SCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCS[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Yield: 97.4 %

Procedure:
To a solution of 0.90 g of 3β-(2-hydroxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol, in 9 ml of dry pyridine, 0.64 g of tosylchloride were added. After 5 hrs 10 ml of water and 50 ml of ethyl acetate were added. The organic phase was washed with water, dried over anhydrous sodium sulfate to give 1.2 g of 3β-(2-tosyioxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol as a colourless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:14][C@@H:15]1[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:18]([CH2:30][OH:31])[C@H:17]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:16]1)(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([O:14][C@@H:15]1[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:18]([CH:30]=[O:31])[C@H:17]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:16]1)(=[O:13])[CH3:12]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A solution of oxalyl chloride (28.3 ml, 324 mmol) in dichloromethane (325 ml) was cooled in a dry ice-methanol bath. Dimethylsulfoxide (46.0 ml, 648 mmol) was added drop wise and the mixture was stirred for approximately 30 minutes. A solution of methyl 7-[(1R,2S,3R,5S)-5-acetoxy-2-hydroxymethyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (28) (65.00 g, 162.3 mmol) in dichloromethane (170 ml) was added Lhereto drop wise and the mixture was stirred for approximately 1.5 hours. Triethylamine (113 ml, 811 mmol) was added drop wise to the reaction and the reaction mixture was warmed to 0° C. Water (426 ml) was added to the reaction mixture and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with t-butyl methyl ether (266 ml). The organic layers were combined and sequentially washed with 1N-hydrochloric acid (390 ml), water (426 ml), saturated sodium bicarbonate water (426 ml) and saturated aqueous sodium chloride (426 ml). After drying with anhydrous magnesium sulfate (54 g), the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 1950 g; ethyl acetate:hexane=3:7) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (59.74 g, 149.9 mmol; yield: 92.4%) as yellow oil.
Reaction SMILES: COC(=O)[CH2:4]/[CH:5]=[C:6](\[CH3:18])/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15].COC(=O)C/C=C(/C)\CC/C=C(\C)/CCC=C(C)C>>[CH3:4][CH2:5][C:6]([CH2:7][CH2:8]/[CH:9]=[C:10](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])\[CH3:17])=[CH2:18]
Reactant: COC(=O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: COC(=O)C/C=C(/C)CC/C=C(\C)CCC=C(C)C
Product: C=C(CC)CC/C=C(\C)CCC=C(C)C

Procedure:
In a 300 ml/500 bar reactor Premex were placed (E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene (10.0 g, 48.9 mmol) in THF (100 ml). Methanol (2.0 ml, 49.4 mmol), and Pd(Cl)2(tri-2-furylphosphine)2 (157 mg, 0.245 mmol; 0.5 mol %) were added. Then the reactor was sealed and the mixture purged with 3×10 bar of carbon monoxide. While stirring, the autoclave was pressurized to 50 bar with CO and the content heated to 90° C. Once the temperature equilibrated to the set point, the autoclave was pressurized to 70 bar with CO and these conditions were then maintained for 68 h. The crude mixture was concentrated on a rotary evaporator affording 11.7 g of yellow liquid. The crude material was bulb to bulb distilled (0.4 mbar, 170° C.) to give 11.3 g of colorless liquid fraction containing (3E,7E)-methyl-4,8,12-trimethyltrideca-3,7,11-trienoate and (3Z,7E)-methyl-4,8,12-trimethyltrideca-3,7,11-trienoate (87%, 2/1).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O.ClCCl>[CH3:16][C:17]1([C:23]([NH:2][C@H:3]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]2=[O:9])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: N[C@H]1CCCNC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C(=O)N[C@H]2CCCNC2=O)CCCCC1
Reaction time: 18 h
Yield: 41.7 %

Procedure:
(S)-3-Amino-tetrahydropyridin-2-one hydrochloride (2 mmol) and Na2CO3 (6 mmol) in water (25 ml) were added to a solution of 1-methylcyclohexanecarbonyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction was stirred for 18 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane. The combined organic layers were dried over Na2SO4 and reduced in vacuo. The residue was purified by silica column chromatography (EtOAc:hexanes 1:3 to MeOH:EtOAc 1:19) to give as an amorphous solid (199 mg, 42%); νmax/cm−1 3335, 3269 (NH), 1650, 1621 (CO), 1529 (NH); δH (500 MHz, CDCl3) 6.65 (1H, br d, J 5, NH), 6.59 (1H, br s, NH), 4.18 (1H, dt, J 11.5, 5.5, CHNH), 3.30 (2H, td, J6.5, 2.5, CH2NH), 2.52 (1H, ddt, J 13, 5.5, 4.5, lactam CH2), 1.92-1.83 (4H, m, 2× lactam CH and 2× cyclohexane CH2), 1.55-1.23 (9H, m, lactam CH and 8× cyclohexane CH2) and 1.11 (3H, s, CH3); δC (125 MHz, CDCl3) 178.0, 172.3 (CO), 50.4 (NHCHCO), 42.6 (CH3C quat), 41.5, 35.6, 35.5, 27.0 (CH2), 26.3 (CH3), 25.7, 22.8 (×2), 20.9 (CH2): m/z (MNa+ C13H22N2O2Na requires 261.1579) 261.1570.
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[CH:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[F:30])[CH3:19].C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:17]#[C:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:13][C:12]3([CH3:14])[CH3:15])=[CH:25][C:24]=1[F:30])[CH3:19]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1F
Yield: 47.4 %

Procedure:
Following general procedure F and using 2-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13 g, 0.571 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.16 g, 0.52 mmol), triethyl amine (0.8 mL), anhydrous tetrahydrofuran (2 mL), copper(I)iodide (0.051 g, 0.27 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0. 1 g, 0. 14 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, 0.1 g of the title compound was obtained as an oil. It was further purified by preparative normal phase HPLC on a partisil-10 silica column using 10% ethyl acetate in hexane as the mobile phase (0.055 g, 24%).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[C:12](#[N:15])[CH:13]=[CH2:14].[OH-].[K+]>O>[C:12]([CH2:13][CH2:14][N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])#[N:15]
Reactant: C=CC#N
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1CCC#N
Temperature: 50 °C
Yield: 46.4 %

Procedure:
To a solution of methyl (4R)-4-hydroxy-L-prolinate hydrochloride (4.53 g, 25 mmol) in water (10 mL) was added acrylonitrile (6.63 g, 125 mmol). The mixture was stirred while heating at 50° C., and a solution of potassium hydroxide (1.403 g, 25 mmol) in water (15 mL) was added dropwise. The resulting mixture was heated to 70° C. and stirred for two hours. The cooled mixture was extracted with diethyl ether (4×25 mL). The combined ether extracts were dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 2-5% methanol in dichloromethane to obtain desired the title compound as colorless oil (2.3 g, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.95-4.87 (m, 1H), 4.26-4.17 (m, 1H), 3.62 (s, 3H), 3.50 (t, J=7.6, 1H), 3.27-3.15 (m, 1H), 2.98-2.87 (m, 1H), 2.76-2.66 (m, 1H), 2.67-2.56 (m, 2H), 2.41-2.33 (m, 1H), 1.99 (ddd, J=12.8, 7.4, 6.4, 1H), 1.93-1.83 (m, 1H); MS (ESI) m/z 199 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[N:12]2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][O:26][C:22]1[N:23]=[C:24]([N:14]2[CH:15]=[CH:16][C:11]3=[N:10][C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:18][N:12]3[C:13]2=[O:17])[CH:25]=[CH:20][N:21]=1
Reactant: O=c1[nH]ccc2nc(COc3ccccc3)cn12
Reactant: COc1nccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1nccc(-n2ccc3nc(COc4ccccc4)cn3c2=O)n1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 19.9 %

Procedure:
Palladium(II)acetate (4.2 mg, 0.019 mmol) was added to a stirred suspension of 2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (150 mg, 0.62 mmol), 4-chloro-2-methoxy-pyrimidine (107.9 mg, 0.75 mmol), Cs2CO3 (283.6 mg, 0.87 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triiso-propyl-1,1′-biphenyl (26.7 mg, 0.056 mmol) in 1,4-dioxane (2 mL) under nitrogen and in a sealed tube. The mixture was stirred at 100° C. for 3 days and at 140° C. for 15 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with diethyl ether to yield 6-(2-methoxy-pyrimidin-4-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (43 mg, 20% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.09 (s, 3H), 5.18 (d, J=0.9 Hz, 2H), 6.77 (dd, J=8.2, 0.6 Hz, 1H), 6.95-7.06 (m, 3H), 7.27-7.36 (m, 2H), 7.85 (d, J=0.7 Hz, 1H), 7.91 (d, J=5.5 Hz, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.65 (d, J=5.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]2[C:9](=[O:22])[N:10]3[CH2:21][CH2:20][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([NH2:19])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1>[F:24][C:2]([F:1])([F:23])[C:3]1[C:8]2[C:9](=[O:22])[N:10]3[CH2:21][CH2:20][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Temperature: 25 °C
Yield: 52.8 %

Procedure:
7.5 g (22.3 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide were suspended in 40 ml of dioxan and 4 ml of pyridine and treated dropwise with 3.6 ml of trifluoroacetic anhydride at 7 to 10° within 10 min. The mixture was stirred at room temperature for 3/4 hour and poured into 300 ml of water. The suspension obtained was filtered and, after drying the residue, there were obtained 3.75 g (52%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile of m.p. 115°-119°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:16][CH2:17]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)O)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of (S)-methyl 5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinate (Example 156, Step A; 0.50 g, 0.95 mmol) in THF (20 mL) was added a 3 M solution of LiOH (3 mL) and the reaction was stirred overnight at ambient temperature. The THF was removed with a stream of nitrogen. The aqueous layer was acidified to pH 1 by the addition of 1 N HCl. The solids that formed were filtered, washed with water and dried under vacuum to give (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinic acid (0.40 g, 82% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]#[C:19][C:20]2[C:21]([NH2:29])=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=2)[CH:15]=[CH:16][CH:17]=1.O1CCCC1>CN(C)C=O>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=[C:20]3[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COCCOc1cccc(C#Cc2cc([N+](=O)[O-])cnc2N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1cccc(-c2cc3cc([N+](=O)[O-])cnc3[nH]2)c1
Temperature: 70 °C
Yield: 83 %

Procedure:
Potassium tert-butoxide (1.18 g, 10.5 mmol) was added to a solution of 3-[3-(2-methoxy-ethoxy)-phenylethynyl]-5-nitro-pyridin-2-ylamine (1.57 g, 5 mmol) in a 2:1 mixture of tetrahydrofuran and dimethylformamide (75 mL). The mixture was heated at 70° C. for 16 hours then the tetrahydrofuran was removed in vacuo. The mixture was poured onto a pad of silica and eluted with ethyl acetate then 10% methanol in ethyl acetate. The organics were concentrated in vacuo to 5% of their original volume and water (30 mL) was added. The resultant orange solid was filtered and dried to afford 2-[3-(2-methoxy-ethoxy)-phenyl]-5-nitro-1H-pyrrolo[2,3-b]pyridine (1.3 g, 83%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.[CH:19](Br)([Br:21])[Br:20]>C1COCC1>[Br:20][CH:19]([Br:21])[C:11]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][C:14]([CH3:15])=[C:9]([O:8][CH3:7])[N:10]=1
Reactant: COc1ncc([N+](=O)[O-])cc1C
Reactant: BrC(Br)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1nc(C(Br)Br)c([N+](=O)[O-])cc1C
Yield: 93.9 %

Procedure:
To a 3 neck, 22 L round bottom flask equipped with a mechanical stirrer and an addition funnel was added potassium t-butoxide (450 g, 4.00 mol) and THF (4 L). The mixture was stirred vigorously and a solution of 2-methoxy-3-methyl-5-nitropyridine (100 g, 0.595 mol) from Part I and bromoform (195.4 g, 0.773 mol) in 500 mL of dry THF was added dropwise at such a rate that the temperature did not rise above −74° C. (3 h addition time). The reaction mixture was stirred at −78° C. for an additional 15 min. The reaction mixture was then quenched by the dropwise addition of a mixture of methanol (400 ml) and conc. HCl (600 mL) while maintaining the temperature below −68° C. Water (1 L) was then added and the aqueous layer was extracted with EtOAc (3×4 L). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (0%→7% ethyl acetate in hexanes) to give 2-(dibromomethyl)-6-methoxy-5-methyl-3-nitropyridine (190.0 g, 94% yield) as a red-brown solid: mp 58.7-61.2° C. 1H NMR (300 mHz, CDCl3) δ 8.04 (s, 1H), 7.60 (s, 1H), 4.15 (s, 3H), 2.26 (s, 1H); LRMS, (ESI) m/e 339.0 [(M+H)+, calcd for C8H9N2O3Br2, 338.9].