Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CCOC(C)=O>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]=1)(=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: COc1ccc2c(C(=O)C(C)C)n[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(C(=O)C(C)C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 5.456 g of 1-(6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one in 100 mL anhydrous DMF. Weigh in 8.96 g cesium carbonate followed by 4.593 g ethyl bromoacetate. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Partition the residue between EtOAc and water. Extract the aqueous layer with EtOAc several times. The combined organic extract was washed with water (3×) and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the crude product. The title compound was obtained by recrystallization from 40 mL 4:1 hexanes and EtOAc. 1H NMR (CDCl3, 500 MHz) δ 8.26 (d, 8.9 Hz, 1H), 7.00 (dd, 2.1 & 9.0 Hz, 1H), 6.685 (d, 2.1 Hz, 1H), 5.17 (s, 2H), 4.28 (q, 7.1 Hz, 2H), 3.90 (s, 3H), 3.87 (heptet, 6.9 Hz, 1H), 1.29 (t, 7.1 Hz, 3H), 1.28 (d, 6.8 Hz, 6H). LC-MS: 3.51 min. (m/Z=305.1, 327.0).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[C:16]#[N:17]>>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1Cl

Procedure:
4-(2-Chloro-4-cyanophenoxy)-3-methoxybenzaldehyde was prepared from vanillin and 3-Chloro-4-fluorobenzonitrile following General Procedure A. 1H NMR (400 Hz, CDCl3) δ 9.95 (s, 1H), 7.76 (d, 1H), 7.56 (br s, 1H), 7.50 (d, 1H), 7.45 (brd, 1H), 7.15 (d, 1H), 6.78 (d, 1H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[H-].[Na+].[CH2:14](Br)[C:15]#[CH:16].O>CN(C)C=O>[CH2:16]([N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: CCOC(=O)CNC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(CC(=O)OCC)C(=O)OC
Reaction time: 2 h
Yield: 64.6 %

Procedure:
100 g of ethyl N-methoxycarbonylglycinate were dissolved in 600 ml of N,N-dimethylformamide. Then ice-cooling the mixture, 25 g of sodium hydride (60% oil dispersion) were added thereto under a nitrogen atmosphere. After the reaction mixture was stirred for 2 hours, 81.3 g of propargyl bromide were dropped thereto over 2 hours. After the mixture was further stirred for an hour, the reaction product was poured into water and the aqueous layer was washed with hexane. Then it was subjected to three times of extraction with 100 ml of ether. The ether layers were combined together and dried over anhydrous magnesium sulfate and the solvent was evaporated off to obtain 79.8 g of ethyl N-propargyl-N-methoxycarbonylglycinate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N+:16]([O-])=O)=[C:11]([CH3:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)CC.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:8][C:9]1[CH:10]=[C:11]([CH3:19])[C:12](=[CH:13][C:14]=1[CH3:15])[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Cl)c(C(C)(C)C)c1
Agent: [Pd]
Agent: NN
Solvent: CCCO
Solvent: O
Product: Cc1cc(Oc2ccc(Cl)c(C(C)(C)C)c2)c(C)cc1N
Temperature: 25 °C

Procedure:
A solution of 40 g (119 mmol) of 4-(3-t-butyl-4-chlorphenoxy)-2,5-dimethylnitrobenzene in 30 ml of n-propanol was treated dropwise with hydrazine hydrate (17.3 ml, 356 mmol), then Pd/C was added (5% on charcoal, 400 mg, 0.2 mmol of Pd) and the mixture was heated to reflux for 10 hrs. After cooling to room temperature the mixture was filtrated, the residue was washed with methanol and the combined filtrates were evaporated. The residue was dissolved in dichloromethane, and the solution was extracted several times with water in order to remove remaining n-propanol. The organic phase was dried over Na2SO4, filtrated and evaporated. Yield: 32 g (87%); log P (pH 2.3)=4.38.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])\[CH3:5].[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]1([C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1)[CH3:5]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C/C(=C\CCl)c1cccc(C#N)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1

Procedure:
To a solution of 3-[(E)-3-chloro-1-methyl-1-propenyl]benzonitrile (Preparation 34, 13.1 g, 69.6 mmol) in dichloromethane (20 ml) was added rhodium (II) acetate dimer (0.46 g, 1.0 mmol). To the mixture was added dropwise at room temperature over 8 h (via a syringe pump) a solution of ethyl diazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml). The solvent was removed in vacuo and the crude residue was then partially purified by silica column chromatography eluting with dichloromethane:hexane (80:20). This material was then dissolved in dichloromethane (20 ml) containing rhodium (II) acetate dimer (0.46 g, 1.0 mmol). To this mixture was added dropwise a solution of ethyl diazoacetate (14.6 ml, 0.14 mol) in dichloromethane (20 ml) at room temperature over 8 h. The mixture was concentrated in vacuo and the residue purified by silica column chromatography eluting with hexane:dichloromethane (80:20) and then hexane:diethyl ether (80:20) to give the title compound as a colourless oil which solidified on standing (5.82 g, 30%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]5([OH:30])[CH2:29][CH2:28]5)=[O:26])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:33]I>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]5([O:30][CH3:33])[CH2:29][CH2:28]5)=[O:26])[CH2:20][CH2:19]4)[CH2:14][CH2:15]3)[C:4]=2[O:3][CH2:2]1
Reactant: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
To trans-1-Hydroxy-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide (20 mg, 48.1 μmol, Eq: 1.00) in THF (500 μl) was added NaH (3.37 mg, 84.2 μmol, Eq: 1.75) and methyl iodide (17.1 mg, 7.52 μl, 120 μmol, Eq: 2.5). After 2 hours the reaction mixture was diluted with water (300 ul). The crude reaction mixture was concentrated in vacuo. The residue was suspended with 5 mL sat NaHCO3 and extracted with dichloromethane (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as an off-white solid (12.1 mg, 58.5%), MS (ISP) m/z=430.2 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Reactant: CS(=O)(=O)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cnc3c(NCCS(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Temperature: 160 °C

Procedure:
To a stirred solution of 1.12 g (2.5 mmol) 4-[6-bromo-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methyl benzamide which was prepared according to intermediate example 516b in 15 mL NMP is added 924 mg (7.5 mmol) 2-(methylsulfonyl)ethanamine and 1.94 g (15 mmol) DIPEA and the mixture is heated at 160° C. for 4 h in a heating block. After working up and without further purification 1.18 g (96%) of the title compound are obtained.
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.F[C:7]1[CH:8]=[C:9]([CH:12]=[C:13](C#CC2C=CC=CN=2)[CH:14]=1)C#N>C(=O)(O)[O-].C([N+](CC)(CC)CC)C.C(Cl)Cl>[C:4]([NH2:2])(=[O:5])[C:7]1[CH:8]=[CH:9][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cc(F)cc(C#Cc2ccccn2)c1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])O
Solvent: ClCCl
Product: NC(=O)c1ccccc1

Procedure:
A DMF (1 mL) solution of 3-fluoro-5-(pyridin-2-ylethynyl)benzonitrile (50 mg, 0.22 mmol) and tetraethylammonium bicarbonate (0.44 mmol) was heated at 120° C. for 10 min. The yellow reaction mixture was cooled and diluted with DCM (10 mL) and washed with aqueous LiCl (5% w/v, 3×5 mL), water (3×5 mL), brine and dried over anhydrous MgSO4. Removal of DCM under reduced pressure yielded quantitative benzamide as a white solid; mp 175-176° C. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): δ 8.63 (d, J=4.9 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.88 (td, J=7.8, 1.7 Hz, 1H), 7.76-1.52 (m, 4H), 7.44 (m, 1H) ppm 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 166.0, 162.0 (d, JCF=246.6 Hz), 150.78, 142.17, 137.68 (d, JCF=8.0 Hz), 137.41, 128.06, 127.47, 124.45, 123.85 (d, JCF=9.1 Hz), 121.34 (d, JCF=22.7 Hz), 116.17 (d, JCF=22.7 Hz), 90.56, 86.83 ppm HRMS (m/z): [M+H]+ calc. for C14H10F2O, 241.0772. found 241.0783.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:12][CH2:13][S:14][CH2:15][CH2:16]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCSCCO)c1cc(F)ccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCSCC1
Yield: 64 %

Procedure:
In toluene (50 ml) was dissolved 2-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol (800 mg, 2.00 mmol), followed by the addition of cyanomethylenetri-n-butylphosphorane (1.50 g, 6.22 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, it was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (504 mg, 1.28 mmol, 64%) was obtained as a white powder.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Br:9][C:10]1[N:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=1>>[Br:9][C:10]1[N:15]=[C:14]([C:16]([N:5]2[CH2:6][CH2:7][O:8][C@H:3]([CH3:2])[CH2:4]2)=[O:17])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: C[C@@H]1CNCCO1
Agent: Cl
Product: C[C@@H]1CN(C(=O)c2cccc(Br)n2)CCO1

Procedure:
The title compound was prepared as described in Example 283, Step 1 using (2R)-2-methylmorpholine hydrochloride (124 mg, 0.90 mmol) and 6-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:20]=[CH:19][C:18]=23)=[O:13])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH2:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH:37][C:6]([C:5]1[CH:9]=[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:20]=[CH:19][C:18]=23)=[O:13])[C:2]([CH3:1])=[N:3][CH:4]=1)=[O:8]
Reactant: CC1(C)CCCN1CCN
Reactant: Cc1ncc(C(=O)O)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(C(=O)NCCN2CCCC2(C)C)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stirring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound;
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14].C(OCC)C>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 4-acetylpyridine (23 mL) in 350 mL toluene was added 55 mL N,N-dimethylformamide dimethyl acetal. The solution was refluxed for 3 hours and allowed to stir at ambient temperature overnight. An additional 33 mL N,N-dimethylformamide dimethyl acetal of was added. After refluxing for 7 hours, the mixture was concentrated to leave an orange solid. This material was treated with diethyl ether. The resulting yellow solid was collected by vacuum filtration. A total of 25.85 g (71% yield) yellow solid was obtained. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS indicated a single peak with a M+1 molecular ion of m/z 177.1 by positive ESI (electrospray ionization mass spectrometry).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:14]2[N:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19](=[O:25])[C@@H:18]([CH2:26][CH3:27])[N:17]([CH:28]([CH3:30])[CH3:29])[C:16]=3[N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[Cu](C#N)[C:32]#[N:33].N(OCCC(C)C)=O>C(#N)C>[CH2:26]([C@H:18]1[N:17]([CH:28]([CH3:29])[CH3:30])[C:16]2[N:15]=[C:14]([C:4]3[S:3][C:2]([C:32]#[N:33])=[N:6][C:5]=3[C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[N:23]=[CH:22][C:21]=2[N:20]([CH3:24])[C:19]1=[O:25])[CH3:27]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3sc(N)nc3-c3ccc(F)cc3)nc2N1C(C)C
Reactant: N#C[Cu]C#N
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3sc(C#N)nc3-c3ccc(F)cc3)nc2N1C(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(2-amino-4-(4-fluorophenyl)thiazol-5-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 318, 0.25 g, 0.586 mmol) and copper cyanide (0.054 g, 0.598 mmol) in 19 mL of anhydrous acetonitrile, isoamyl nitrite (0.1 ml, 0.751 mmol) was added. The reaction was placed in an oil bath set at 90° C. under condenser with N2 (g) inlet. The reaction mixture was stirred for 1 h, then cooled and quenched with water and extracted with EtOAc. The organic phase was collected, dried with sodium sulfate, filtered and concentrated. The resulting material was purified by preparative HPLC to give the title compound. LCMS: 437.1 m/z (M+H)+; ret. Time: 7.85 min (Analytical Method A). 1H NMR (CDCl3) δ: 7.83 (s, 1H), 7.69 (d, J=6 Hz, 1H), 7.67 (d, J=6 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 4.33-4.28 (m, 1H), 4.20-4.14 (m, 1H), 3.37 (s, 3H), 2.07-2.02 (m, 1H), 1.94-1.85 (m, 1H), 1.24 (d, J=7 Hz, 3H), 1.13 (d, J=7 Hz, 3H), 0.84 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([Cl:37])=[CH:39][CH:40]=3)=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3-{4-Amino-2-[(benzyloxycarbonyl-ethyl-amino)-methyl]-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester (0.1 g, 0.19 mmol), 4-chlorobenzoyl chloride (0.1 g, 0.57 mmol), and triethylamine (0.5 mL, 3.6 mmol) were combined in CH2Cl2 (10 mL) and stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound.
Reaction SMILES: C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)C[OH:10])=CC=C([N+]([O-])=O)C=1.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]>>[NH:21]1[CH2:28][C@H:27]([OH:10])[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
A plasmid (pHuCol(α1)Ec, FIG. 65) containing the gene for Type I (α1) collagen with optimized E. coli codon usage (FIG. 39A-39E) (SEQ. ID. NO. 19) under control of the tac promoter and containing the gene for chloramphenicol resistance was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 20 μg/ml chloramphenicol. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 100 ml of LB media containing 20 μg/ml chloramphenicol. This culture was grown to an OD600nm of 0.5 and 100 μl aliquots transferred to 1.5 ml tubes. The tubes were stored at −80° C. For expression, a tube was thawed on ice and used to inoculate 25 ml of LB media containing 20 μg/ml chloramphenicol. After overnight growth at 37° C., a four ml aliquot was withdrawn, centrifuged, the cell pellet washed once with 1 ml of 2×YT media containing 20 μg/ml chloramphenicol, and the washed cells used to inoculate 1 L of 2×YT medium containing 20 μg/ml chloramphenicol. This culture was grown at 37° C. to an OD600nm of 0.8. The culture was centrifuged and the cell pellet washed once with 100 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chloramphenicol). The cells were resuspended in 910 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chlorarnphenicol) and allowed to grow at 37° C. for 30 minutes. NaCl (80 ml of 5 M), hydroxyproline (7.5 ml of 2M), and IPTG (500 μl of 1 M) were added and growth continued for 3 hours. Cells were harvested by centrifugation and stored at −20° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:4]=[CH:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:13])[C:11]=2[CH:12]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][NH:23][C:24]([NH:13][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:12]=[C:3]([C:2]([F:1])([F:14])[F:15])[N:4]=[CH:5]3)=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1cccc2cnc(C(F)(F)F)cc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2cnc(C(F)(F)F)cc12

Procedure:
Prepared from 3-(trifluoromethyl)isoquinolin-5-amine (Description 64) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 414 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O>>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=Cc1ccc(O)c(Br)c1
Product: O=C(C=Cc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(3-Bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 3-bromo-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is crystallized from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:37](OCC)(=O)C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[CH3:37])[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(benzyloxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (830 mg) was added 4 M hydrogen chloride/ethyl acetate (20 mL), and the reaction mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF and methanol, and the solution was subjected to NH silica gel column chromatography (ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (660 mg).