Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][S:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([N:23]=O)=[C:18]([NH2:25])[N:17]=1.[O:26]1CC[CH2:28][CH2:27]1>CN(C)C=O>[NH2:25][C:18]1[C:19]2[N:23]=[CH:28][C:27](=[O:26])[NH:22][C:20]=2[N:21]=[C:16]([S:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[N:17]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Temperature: 25 °C

Procedure:
To a solution of triethyl phosphonoacetate (15.0 g) in tetrahydrofuran (60 ml) cooled in an ice bath was added butyllithium (2.5 M in hexanes, 25.6 ml) at a rate such that the internal temperature was maintained below 30° C. To this mixture was then added a solution of the product of Example 2 step (b) (10.0 g) in N,N-dimethylformamide (60 ml). The reaction mixture was heated at reflux for 1 hour, then cooled to room temperature and quenched with acetic acid (6 ml). The solid thus precipitated was isolated by filtration, washed with water, ethanol and diethyl ether, and dried over P2O5 at 50° C. to give the sub-titled product as a pale green solid (9.3 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:10]=2)[CH:7]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.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>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccccc1-c1nnc2ccc(Br)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nnc2ccc(-c3ccc(C)cc3)cn12
Yield: 86.3 %

Procedure:
To a solution of 6-bromo-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.329 mmol) in toluene (20 mL) and water (5 mL) was added 4-methylphenylboronic acid (67.1 mg, 0.493 mmol), Pd(PPh3)4 (18.4 mg, 0.016 mmol) and Cs2CO3 (55.3 mg, 0.658 mmol), and the reaction mixture was refluxed under Argon overnight. The mixture was filtered and the filtrate was washed with water (50 mL×2), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1) to give the title compound (89.5 mg, 50.6% yield) as yellow solids. 1H NMR (DMSO-d6): 8.09 (m, 1H), 7.93 (dd, J=9.6 and 0.9 Hz, 1H), 7.77 (d, J=9.6 and 1.8 Hz, 1H), 7.64-7.58 (m, 4H), 7.33-7.28 (m, 3H), 7.19 (t, J=7.2 Hz, 1H), 3.85 (s, 3H), 2.35 (s, 3H). MS: m/z 316.2 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:19]=[C:18]2[C:9]([NH:10][C:11]3[C:16]([S:17]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=12.C(OCC)C>CN(C=O)C>[C:1]([N:10]1[C:9]2[C:18](=[CH:19][C:6]([OH:5])=[C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]3=2)[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:3])[CH3:2]
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (2 ml) was added to a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1) (2.65 gm) in DMF (10 ml) and stirred for 30 minutes. Diethyl ether (100 ml) was added to the reaction mixture followed by ice-water (50 ml). The aqueous layer was decanted and the organic layer containing a solid was evaporated to dryness. The resulting residue was treated with acetone and filtered to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C@@H:13]3[C@@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46](O)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:46]([O:19][C@H:18]1[C@@H:13]2[N:14]([N:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:12]2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:16][CH2:17]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2=NN3CC[C@@H](OC(=O)c4ccccc4)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile (80 mg, 0.235 mmol) in THF (3 mL) were added PPh3 (123 mg, 0.470 mmol), benzoic acid (58 mg, 0.470 mmol) and DIAD (0.09 mL, 0.470 mmol) and the reaction mixture was stirred at room temperature for 3 h. Then it was diluted with ethyl acetate and washed with saturated NaHCO3 solution, water, and brine, then dried over Na2SO4 and concentrated to get the crude product which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:27][O:26][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][S:36]([CH3:35])(=[O:38])=[O:37])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OS(C)(=O)=O
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) in dichloromethane (15 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract with aqueous 1M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH2:23][CH2:24][CH3:25]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:22]([CH3:21])[CH2:23][CH2:24][CH3:25])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCNC
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-methyl-propylamine (3.72 ml, 34.7 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.75 g, 75%).
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH:20]([CH3:29])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:20]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:29])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)c1ccccc1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 1516.1 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (7.73 g, 26.3 mmol), 2-bromo-1-phenylpropan-1-one (5.94 ml, 39 mmol) and K2CO3 (12.7 g, 92 mol) was treated according to general preparation 2, then recrystallized with ethanol to give 85 g of N1-(4-nitrobenzyl)-N4-(1-benzoylethyl)piperazine dihydrochloride, yield 70%, mp 256-8° C., which was reduced by reductive iron in the similar procedure of Example 12, to give compound (IV-13), yield 65%, mp 244-246° C. (dec). M+ 323.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].N1C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[C:38]([NH:1][C:2]1[C:3]([F:31])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:9]([CH3:25])=[CH:10][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:17])[F:19])=[CH:12][C:13]=1[CH3:14])=[O:6])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(NC(=O)c2ccccc2)c1F
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 3-amino-4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-fluoro-benzamide (68 mg, 0.15 mmol) (Example I12) in tetrahydrofuran (2 ml) were added pyridine (36 μl, 0.45 mmol) and benzoyl chloride (21 μl, 0.18 mmol). The reaction mixture was heated in a microwave at 140° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature. A second portion of benzoyl chloride (21 μl, 0.18 mmol) was added and heating repeated at 140° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then partitioned between sodium hydrogen carbonate (1M) and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase chromatography (eluent: trifluoroacetic acid/water/acetonitrile 1:4:5 to 1:1:8) to give Compound No. D15 of Table D (0.024 g, 28% yield). 1H-NMR (400 MHz, CDCl3): 2.28 (6H, s), 7.33 (2H, s), 7.45-7.96 (9H, m) ppm.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:14][CH:15]=[CH:16][C:17]=2[CH3:18])[CH2:6]1)C.C(=O)(O)O.[NH2:33][C:34]([NH2:36])=[NH:35].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:13]2[C:12]([N:7]3[CH2:8][CH2:9][C:10]4[N:35]=[C:34]([NH2:36])[N:33]=[CH:4][C:5]=4[CH2:6]3)=[C:17]([CH3:18])[CH:16]=[CH:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: N=C(N)N
Reactant: COc1ccc(COc2nccc(C)c2N2CCC(=O)C(=CN(C)C)C2)cc1
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(COc2nccc(C)c2N2CCc3nc(N)ncc3C2)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 3-dimethylaminomethylene-2′-(4-methoxybenzyloxy)-4′-methyl-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (5.21 g, 13.66 mmol) in methanol (340 ml) was treated with guanidine carbonate (9.84 g, 54.63 mmol), followed by addition of sodium acetate trihydrate (14.87 g, 109.28 mmol) and the reaction mixture was refluxed for 3 hours. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The separated organic layer was dried (MgSO4), filtered, and concentrated to a red oil. The oil was taken up in a minimal volume of EtOAc and allowed to stand overnight at room temperature. The resulting yellow, crystalline solid was collected, washed with EtOAc, and dried to give the title compound (1.91 g). The mother liquor was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, EtOAc) to obtain an additional lot of the title compound (1.05 g) The total amount 2.96 g, 57%). HPLC analysis showed the compound has a purity of 98%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[H][H]>[Ni].CO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Reaction time: 30 h

Procedure:
45 g of Raney nickel are added to 254.2 g of 3-cyano-3-phenylglutaric acid diethyl ester in 1.5 liters of absolute methanol, and hydrogenation is effected in a 5 liter autoclave for 30 hours at 80° and a hydrogen pressure of 81 atmospheres. After cooling, the catalyst is filtered off, the filtrate is concentrated on a rotary evaporator, the resulting light yellow oil is taken up in 1.5 liters of chloroform and is successively washed with 25 cc of 2 N hydrochloric acid, 100 cc of saturated sodium bicarbonate solution and 100 cc of water. The 5-oxo-3-phenyl-3-pyrrolidine acetic acid ethyl ester, obtained after concentrating the chloroform phase, crystallizes upon triturating with ether. M.P. 49°-51° (from ethyl acetate/petroleum ether).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and pyridin-3-ylboronic acid. HPLC (Condition 4) tR=4.38 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=445.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.68 (m, 1H) 3.37-3.49 (m, 4H) 3.68 (t, J=8.41 Hz, 2H) 4.66 (t, J=5.28 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.49 (dd, J=7.82, 4.69 Hz, 1H) 7.84 (d, J=8.99 Hz, 3H) 7.99 (d, J=2.35 Hz, 1H) 8.54-8.60 (m, 1H) 8.64 (d, J=1.96 Hz, 1H) 8.72-8.78 (m, 1H) 10.18 (s, 1H).
Reaction SMILES: [P:1]([CH2:5][NH:6]CC(O)=O)([OH:4])([OH:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.N.Cl[C:22]([O:24][CH2:25][O:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[O:23]>C(Cl)Cl>[C:27]([CH2:28][O:4][P:1]([CH2:5][NH:6][C:22]([O:24][CH2:25][O:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[O:23])([OH:3])=[O:2])([OH:31])=[O:26]
Reactant: CC(C)C(=O)OCOC(=O)Cl
Reactant: O=C(O)CNCP(=O)(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Solvent: ClCCl
Product: CC(C)C(=O)OCOC(=O)NCP(=O)(O)OCC(=O)O
Temperature: 125 °C
Reaction time: 12 h

Procedure:
A stirred solution of phosphonomethyl glycine (9.49 g, 56.2 mmol) in hexamethyldisilazane (25.5 mL, 121 mmol) was slowly heated to 90° C. (at this temperature it was noted out gassing of ammonia occurred). The reaction temperature was increased to 125° C. for 150 min at which time the reaction became homogeneous. The solution was allowed to cool to room temperature at which time, dry methylene chloride (60 mL) was added. The material (34.0 g, 74.5 mmol) was syringed into a flask and placed under a N2 atm. Methylene chloride (120 mL) was added and the solution cooled in a dry ice acetone bath. A solution of 2-methylpropanoic acid chlorocarbonyloxymethyl ester (10.7 g, 59.1 mmol) in 5 mL of methylene chloride was added dropwise over two minutes through a 3 mL syringe. After 10 minutes the cooling bath was removed and the reaction was allowed to warm to room temperature and stir for 12 h. The reaction solution was concentrated under reduced pressure and dissolved in 200 mL of methanol and allowed to stand for 4 h. The reaction was vacuum filtered and concentrated under reduced pressure. The oil was dissolved with 120 mL of dry acetone and allowed to stand for one hour, vacuum filtered, and concentrated under vacuum. The solid was triterated with 60 mL of warm hexanes and then placed under vacuum. Yield 14.0 grams. 1H-NMR (300 MHz, D2O) δ (ppm): 1.01 (dd, 6H), 2.51 (m, 1H), 3.47 (d, 2H), 4.09 (d, 2H), 5.63 (d, 2H).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH3:23])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:23][O:22][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:24])=[O:2])=[CH:10][CH:9]=3)=[CH:18][CH:17]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC1(c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Using General Procedure I; a solution of methyl{4-[4-(1-methoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 68, 100.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 80.0 mg (84%) of the title compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(=O)C)[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[CH2:17]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:17]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[O:16][C:3]1[C:2]([Br:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:15])[NH:8]2)[CH:18]=[CH2:19]
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: C=CCn1c(Br)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCn1c(Oc2c(Br)ccc3c2CC[C@H](C)N3)nc2ccccc21
Temperature: 200 °C
Yield: 40.7 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 0.71 mmol), 1-allyl-2-bromo-1H-benzo[d]imidazole (0.340 g, 1.44 mmol), and potassium carbonate (0.293 g, 2.12 mmol) in N,N-dimethylacetamide (10 mL) was heated in the microwave for 2 h at 200° C. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 20% ethyl acetate/petroleum ether) to afford (S)-5-(1-allyl-1H-benzo[d]imidazol-2-yloxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinoline (0.115 g, 41%) of as a light yellow solid. MS (ESI, pos. ion) m/z 398, 400 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])[CH3:26].Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH:31][CH2:2][C:3](=[O:4])[N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[CH3:26]
Reactant: O=C(CCl)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCNCC(=O)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Yield: 10 %

Procedure:
A mixture of crude 2-chloro-1-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethanone (80 mg, 0.22 mmol), 3-amino-propionic acid ethyl ester as HCl salt (68 mg, 0.44 mmol) and potassium carbonate (98 mg, 0.71 mmol) in acetonitrile (2 mL) was heated to reflux for 4 hrs. The mixture was treated with water and extracted with ether. The organic phase was dried over MgSO4, concentrated, and purified via a silica gel column to give desired product (11 mg, yield 10%). ESI-MS: 443.20 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH2:16][S:17]C(=O)C)[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:3])[NH2:2]>O.N>[C:1]([CH2:4][CH:5]([CH2:16][SH:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:3])[NH2:2]
Reactant: CC(=O)SCC(CC(N)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: O
Product: NC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
1-[2-Carbamoylmethyl-3-acetylthiopropanoyl]-L-proline (1.2 g.) is dissolved in a mixture of water (20ml.) and concentrated ammonia (20 ml.). After 15 minutes the reaction mixture is processed as described in "A" above to obtain 1-[2-carbamoylmethyl-3-mercaptopropanoyl]-L-proline.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]([CH:20]1[O:24][C:23]([N:25]([CH3:27])[CH3:26])=[N:22][C:21]1=[O:28])[CH3:19])=[CH:12][NH:13]2)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[CH3:27][N:25]([CH3:26])[C:23]1[O:24][CH:20]([CH:18]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[OH:8])[NH:13][CH:12]=2)[CH3:19])[C:21](=[O:28])[N:22]=1
Reactant: CC(c1c[nH]c2cccc(OCc3ccccc3)c12)C1OC(N(C)C)=NC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(c1c[nH]c2cccc(O)c12)C1OC(N(C)C)=NC1=O
Reaction time: 5 h
Yield: 61.3 %

Procedure:
5-[1-(4-benzyloxyindol-3-yl)ethyl]-2-dimethylamino-2-oxazolin-4-one (268 mg) was dissolved in a mixture of ethanol and tetrahydrofuran (7:3.10 ml). 10% palladium-carbon (80 mg) was added and the whole was hydrogenated for 5 hours at room temperature under normal pressure. The catalyst was removed from the mixture and 10% palladium-carbon (80 mg) was added again. The whole was hydrogenated for additional 24 hours at room temperature under normal pressure. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to give 2-dimethylamino-5-[1-(4-hydroxyindol-3-yl)ethyl]-2-oxazolin-4-one (125 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:13]2[CH:22]=C(C(O)=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C:13]2[CH:22]=[C:1]([C:2]([Cl:4])=[O:3])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Temperature: -10 °C
Reaction time: 8 h

Procedure:
11.7 ml (136.3 mmol) of oxalyl chloride were dissolved in 150 ml of CH2Cl2. The solution was cooled at −10° C. and 20 g (80.2 mmol) of commercially available 2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 22 g of the title compound, used without further purification.