Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].NC1C=CC(Br)=CN=1.C(OC(=O)C(SC1SC=C(CC(O)=O)N=1)(C)C)(C)(C)C.[CH2:55](I)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].CC(C)([O-])C.[K+]>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Br)cn2)cs1
Reactant: CCCCCCCI
Agent: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Agent: CC(C)(C)[O-]
Agent: Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
2-[(4-{2-[(5-Bromopyridin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (4.78 g) synthesized in Example 242 from 2-amino-5-bromopyridine and {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid obtained in Example 3, and heptyl iodide (3.54 g) were dissolved in N,N-dimethylformamide (50 mL), potassium tert-butoxide (1.75 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (1.72 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[F:15])=[O:5])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]([F:13])=[C:9]([F:14])[C:8]=1[F:15])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Oc1ccc(F)c(F)c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
9.82 g (44.6 mmol) of the above O-ethoxycarbonyl-2,3,4-trifluorophenol was dissolved in 25 mL of concentrated sulfuric acid under ice-cooling, 8.0 mL of fuming nitric acid was added at an internal temperature of 50° C. or below and the mixture was further stirred for 2 hours. The reaction solution was poured into 300 mL of ice water and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and twice with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give 1.44 g of O-ethoxycarbonyl-2,3,4-trifluoro-5-nitrophenol (yield: 12%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]([CH:29]([CH3:31])[CH3:30])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[O:14])[CH:11]=2)[C:6]([CH3:33])([CH3:32])[C:5]1=[O:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:56][CH:57]([F:61])[C:58](O)=[O:59]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:56][CH:57]([F:61])[C:58]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]([CH:29]([CH3:30])[CH3:31])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]3)=[O:14])[CH:11]=2)[C:6]([CH3:32])([CH3:33])[C:5]1=[O:34])=[O:59]
Reactant: O=C(O)C(F)F
Reactant: CC(C)N(C(=O)c1ccc2c(c1)N(CCN)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1ccc2c(c1)N(CCNC(=O)C(F)F)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To tert-butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (300 mg) were added WSC (210 mg), HOBt (150 mg), triethylamine (0.30 ml), chloroform (5 ml), and difluoroacetic acid (79 mg), and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (170 mg) as colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].Br[CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[O:28][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(Oc3cccc(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 120B and ethyl 5-bromovalerate were processed as described in Example 116A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:10][C@H:9]1[CH:11]([NH:13][O:14][CH3:15])[CH3:12].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:10][C@H:9]1[CH:11]([N:13]([O:14][CH3:15])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31])[CH3:12]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
To a stirred solution of trans N-{1-[2-(2-chloro-phenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.30 g; 1.3 mmol) prepared as described in example P12 and triethylamine (0.25 ml; 1.7 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.28 g; 1.3 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (50 ml) and extracted with dichloromethane (3×25 ml). Combined organic layers were washed with water (10 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 0.46 g (92% of theory) of trans 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[2-(2-chloro-phenyl)-cyclopropyl]-ethyl}-methoxy-amide as single diastereomere A in form of a clear viscous oil.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([C:26]=2[OH:27])=[N:24][C:23]([O:28][CH3:29])=[CH:22][CH:21]=3)[CH2:10][CH2:9]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[OH:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[N:24]=2)[N:19]=[CH:18][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([C:39]2[CH:40]=[CH:41][C:35]3[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=3[CH:38]=2)=[O:30])[CH2:9][CH2:10]1
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)c(O)c2n1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)c(O)c2n1

Procedure:
The title compound is prepared as a white lyophilizated powder following Scheme 1 and in analogy to Example 1 using {1-[2-(4-hydroxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][O:2]C1C=CC(C#CC(OCC)=O)=C(OC)C=1C1C(C)=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[C:42][C:43]([OH:45])=[O:44])=[C:37](OC)[C:36]=1[C:48]1[C:57]([CH3:58])=[CH:56][C:55]2[C:54]([CH3:60])([CH3:59])[CH2:53][CH2:52][C:51]([CH3:62])([CH3:61])[C:50]=2[CH:49]=1>>[CH3:1][O:2][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]#[C:42][C:43]([OH:45])=[O:44])=[CH:37][C:36]=1[C:48]1[C:57]([CH3:58])=[CH:56][C:55]2[C:54]([CH3:59])([CH3:60])[CH2:53][CH2:52][C:51]([CH3:62])([CH3:61])[C:50]=2[CH:49]=1
Reactant: COc1ccc(C#CC(=O)O)c(OC)c1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C#Cc1ccc(OC)c(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1OC
Product: COCOc1ccc(C#CC(=O)O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 2(h), starting from 439 mg (1 mmol) of ethyl [4-methoxy-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]propynoate, 375 mg (91%) of [4-methoxy-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]propynoic acid having a melting point of 168°-170° C. were obtained.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5](=[O:24])[CH2:6][C:7]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)(O)[CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[Na+].C(O)(=O)C>CO>[C:14]([O:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][C:7]1([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:6][C:5](=[O:24])[CH2:4][C:3](=[O:2])[O:25]1)([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)CC(=O)CC(O)(CCNC(=O)OC(C)(C)C)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC1(C2CCCC2)CC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To 7-tert-butoxycarbonylamino-5-cyclopentyl-5-hydroxy-3-oxo-heptanoic acid methyl ester (1.36 g, 3.8 mmol) from Step 3 above dissolved in MeOH (50 mL) was added a NaOH solution (2.8 M, 2.7 mL, 7.6 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then quenched with acetic acid (0.44 mL, 7.7 mmol) and concentrated by rotary evaporation to an oil. The oil was dissolved in CH2Cl2 and washed with water. The organic layer was separated, and dried over Na2SO4. The solids were removed by filtration, and the liquid was concentrated to yield the product (1.061 g, 86% yield). MS (ESI): 324 (M−H).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:13]=1.N.[H][H]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:12]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:13]=1
Reactant: O=C(O)CCCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: [H][H]
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCc1cc(Cl)ccc1OCCc1ccccc1
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
246 mg of aluminum lithium hydride was added under ice-cooling to a solution of 1.38 g of the crude 4-[5-chloro-2-(2-phenylethoxy)phenyl]butyric acid in 20 ml of tetrahydrofuran and the resulting mixture was stirred at the same temperature for 30 minutes. Next, 25% aqueous ammonia was added thereto until no hydrogen evolved any more. After filtering with the use of Celite and anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate:n-hexane =1:8) to give 0.86 g of 4-[5-chloro-2-(2-phenylethoxy)phenyl]butanol.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:21][NH2:22]>C(O)C>[CH3:21][NH:22][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: COc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1ncccc1OC

Procedure:
1-Methylthio-1-[2-((3-methoxy-2-pyridyl)methylthio)ethylamino]-2-nitroethylene (1.4g) was stirred with a solution of methylamine in ethanol (25 ml, 33% solution) and dissolved within a minute. After a further 3 minutes a crystalline product separated and recrystallisation from ethanol/ether yielded the title product (1.1 g), m.p. 145.5°-147°.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[N:22]=[C:23]([NH2:42])[C:24]2[CH:30]=[C:29]([CH:31]=[CH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=3)[CH:28]=[N:27][C:25]=2[N:26]=1>>[NH2:20][C:21]1[N:22]=[C:23]([NH2:42])[C:24]2[CH:30]=[C:29]([CH:31]=[CH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([NH:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])=[O:40])=[CH:35][CH:34]=3)[CH:28]=[N:27][C:25]=2[N:26]=1
Reactant: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OC(C)(C)C

Procedure:
Alternatively, 2.2 g (0.0074 mol) of di-tert-butyl L-glutamate hydrochloride were allowed to react with 1.5 g (0.0049 mol) of 2,4-diamino-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine, to yield di-tert-butyl N-(4-[2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoyl)-L-glutamate in a yield of 1.3 g (48%), mp >300° C. NMR (CDCl3 /CD3OD) delta 1.47, 1.52 (2s, 18H), 2.0-2.6 (m, 4H), 4.5-7.0 (m, 1H), 6.8 (br, s, 2H), 7.35, 7.78 (AB q, 4H, J=9 Hz), 8.38 (s, 1H), 8.5 (s, 1H); IR (Nujol) 3350, 3180, 1725, 1640, 1605 cm-1. MS: Calc'd.: for C29H36N6O5 : 548. Found: m/e 548, 446, 290.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[NH2:9][C:10]([NH2:12])=[S:11].C(O)C>C(OCC)(=O)C>[ClH:2].[ClH:1].[CH3:7][N:6]([CH3:8])[CH2:5][CH2:4][CH2:3][S:11][C:10](=[NH:9])[NH2:12]
Reactant: NC(N)=S
Reactant: CN(C)CCCCl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)CCCSC(=N)N
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
A stirred mixture of 1-chloro-3-(dimethylamino) propane hydrochloride (305.7 g), thiourea (150 g) and ethanol (1530 ml) was heated under reflux for 24 hours then cooled to ambient temperature. Ethyl acetate was added until a faint opalescence was observed, then the mixture was stored at 4° C. for 72 hours. The resulting solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at 40° C. to give S-[3-(dimethylamino)propyl]isothiourea dihydrochloride as a white solid (403 g), m.p. 155°-157° C.
Reaction SMILES: O[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:15][C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4][N:5]([C:10]([CH3:14])([C:12]#[CH:13])[CH3:11])[C:6](=[O:9])[O:7]C.Br[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[C:31](=[O:37])[CH:30]=[CH:29]2>>[CH3:14][C:10]([N:5]1[CH2:4][CH2:3][C:2]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:7][C:6]1=[O:9])([C:12]#[C:13][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[C:31](=[O:37])[CH:30]=[CH:29]2)[CH3:11]
Reactant: Cn1c(=O)ccc2cc(Br)ccc21
Reactant: C#CC(C)(C)N(CCC(O)(CC(=C)C)c1ccccc1)C(=O)OC
Product: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)C#Cc2ccc3c(ccc(=O)n3C)c2)C(=O)O1

Procedure:
The title compound was prepared from methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-methylbut-3-yn-2-yl)carbamate and 6-bromo-1-methylquinolin-2(1H)-one following procedures analogous to those described in Example 1 Steps 3 and 4. LC-MS Method 1 tR=1.92 min, m/z=455; 1H NMR (CDCl3) 1.64 (s, 3H), 1.69 (s, 3H), 1.82 (s, 6H), 2.26 (m, 1H), 2.40 (m, 1H), 2.61 (AB quartet, 2H), 3.08 (m, 1H), 3.64 (m, 1H), 3.71 (s, 3H), 4.64 (s, 1H), 4.83 (s, 1H), 6.77 (d, 1H), 7.25-7.65 (9H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][C:17](=O)OC(C)(C)C)=[N:13][CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]([F:55])([F:54])[C:32]1[CH:53]=[CH:52][C:35]([CH2:36][CH:37]2C[N:38]2S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+].SC(O)C>CN(C=O)C>[NH2:38][C@@H:37]([CH2:36][C:35]1[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:54])[F:55])=[CH:53][CH:52]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][N:3]=[CH:4]3)=[CH:12][N:13]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2Cc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3cnncc3c2)s1
Agent: CC(O)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N[C@H](CNc1ncc(-c2ccc3cnncc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of tert-butyl 5-(phthalazin-6-yl)thiazol-2-ylcarbamate (0.320 g, 0.97 mmol) and Cs2CO3 (0.63 g, 1.9 mmol) in DMF was stirred at room temperature for 30 minutes. The resulting solution was treated dropwise with ((S)-2-(4-(trifluoromethyl)benzyl-1-(4-nitrophenylsulfonyl)aziridine in DMF, and was then stirred for 30 minutes. The reaction was treated in portions with K2CO3 (0.67 g, 4.9 mmol) and mercaptoethanol (0.23 g, 2.9 mmol) and stirred for 15 minutes. After removing the solvent under reduced pressure, the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM. The resulting residue was dissolved in DCM and treated with TFA to provide the title compound (0.100 g, 19% yield). LCMS (M+H) 430.6 calc. for C21H18F3N5S 430.6; 1H NMR (400 MHz, CDCl3-d) δ ppm 9.48 (s, 1H), 9.44 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H), 7.75 (s, 1H), 7.62 (sd, 3H), 7.35 (d, 2H), 3.92 (dd, 2H), 3.55 (dd, 1H), 3.25 (tt, 1H) 2.98 (dd, 1H), 2.89 (t, 2H), 2.72 (b, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][C:21]=2[F:28])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4F)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (55 mg, 61%), MS (ISP) m/z=363.4 [(M+H)+], mp 251.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][N:15]([CH2:38][CH2:39][CH2:40][CH3:41])[C:16]([N:18]([CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16](=[O:17])[N:15]([CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:42])[CH2:38][CH2:39][CH2:40][CH3:41])([OH:33])=[O:32]
Reactant: CCCCN(CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)C(=O)N(CCCC)CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(CC(=O)N1CCC[C@@H]1C(=O)O)C(=O)N(CCCC)CC(=O)N1CCC[C@@H]1C(=O)O
Yield: 73.6 %

Procedure:
A solution of 278 mg (0.47 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-1,3-dibutyl-ureido]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue was dried to give 167 mg (74%) of the title compound as brown foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH3:22][C:21]1[CH:20]=[C:19]([O:23][S:33]([CH3:32])(=[O:35])=[O:34])[CH:18]=[C:17]([CH3:24])[C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=2)[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OS(C)(=O)=O)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
To an ice-cooled solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (310 mg, 0.736 mmol) in pyridine (8 mL) was added dropwise methanesulfonyl chloride (168 mg, 1.47 mmol). The mixture was stirred at room temperature for 2 days. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (320 mg, yield 87%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9]>[Pd].CO>[NH2:12][C:6]1[CH:5]=[C:4]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCOc1ccncc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(N)=O)c(N)cc1OCCOc1ccncc1
Temperature: 40 °C
Yield: 100.5 %

Procedure:
5-Methoxy-2-nitro-4-(2-(4-pyridyloxy)ethoxy)benzamide (2.15 g, 6.4 mmol) and 10% palladium-on-charcoal catalyst (100 mg) were suspended in methanol (400 ml) and placed under hydrogen at atmospheric pressure. The reaction mixture was heated at 40° C. for 1 hour, cooled to ambient temperature, filtered through diatomaceous earth and the solvent was removed by evaporation. The precipitate was slurried with ether and collected by filtration to give 2-amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide as a cream solid (1.95 g, 99%). 2-Amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide (1.95 g, 6.4 mmol) and formamide (10 ml) were heated at 190-200° C. for 1 hour. The reaction mixture was allowed to cool to 50° C. as the product precipitated out. Water (50 ml) was added and the solid was collected by filtration, washed with more water and ether and dried under vacuum to give 6-methoxy-7-(2-(4-pyridyloxy)ethoxy)-3,4-dihydroquinazolin-4-one (0.99 g, 49%) as a cream solid. The 6-methoxy-7-(2-(4-pyridyioxy)ethoxy)-3,4-dihydroquinazolin-4-one (312 mg, 1 mmol) was heated at reflux in thionyl chloride (10 ml) and DMF (5 drops) for 1 hour, then evaporated to dryness and partitioned between a saturated solution of sodium hydrogen carbonate and methylene chloride. The methylene chloride phase was dried by filtration through a phase separator paper and the solvent was removed by evaporation to give crude 4-chloro-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline which was used without further purification.