Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([O:14][C:15]([NH:17][C@H:18]([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([CH:48]1[C:52]2[C:53]([O:57][C:58]3[N:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=3)=[CH:54][CH:55]=[CH:56][C:51]=2[CH2:50][O:49]1)[CH3:47]>CN(C)C=O>[CH2:46]([CH:48]1[C:52]2[C:53]([O:57][C:58]3[N:63]=[CH:62][C:61]([NH:64][C:19]([C@H:18]([NH:17][C:15](=[O:16])[O:14][C:11]([CH3:10])([CH3:12])[CH3:13])[CH2:22][CH3:23])=[O:21])=[CH:60][CH:59]=3)=[CH:54][CH:55]=[CH:56][C:51]=2[CH2:50][O:49]1)[CH3:47]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCC1OCc2cccc(Oc3ccc(N)cn3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1OCc2cccc(Oc3ccc(NC(=O)[C@@H](CC)NC(=O)OC(C)(C)C)cn3)c21
Temperature: 60 °C
Yield: 73.7 %

Procedure:
In a 8 ml vial 6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinamine (Intermediate 108, 10 mg) was dissolved in N,N-dimethylformamide (1 ml) to give a colourless solution. DIPEA (10.22 μl, 0.059 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (9.52 mg, 0.047 mmol) and, finally, TBTU (15.03 mg, 0.047 mmol) were added. The reaction mixture was shaken at 60° C. After overnight shaking, the reaction was completed. The reaction mixture was evaporated under vacuum to give the crude product as a yellow oil which was purified via Biotage SP1 (with Cyclohexane/EtOAc as eluents from 2:1 to 1:1 in 10 CV; then 2:1 for 5 CV; 10 g SNAP Silica column). The collected fractions afforded the title compound as a colourless oil (12.7 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:15](=[O:28])[N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:29][C:30]1[CH:31]=[C:32]([CH2:39][C@@H:40]([NH:44][C:45]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][C:54]3=[O:63])[CH2:49][CH2:48]2)=[O:46])[C:41](O)=[O:42])[CH:33]=[C:34]2[C:38]=1[NH:37][N:36]=[CH:35]2.CC1C=C(C[C@@H](NC(N2CCC(C3C(=O)NC4C(C=3)=CC=CC=4)CC2)=O)C(N[C@H](C(=O)N2CCN(C3C=CN=CC=3)CC2)CCCCNC(=O)OC(C)(C)C)=O)C=C2C=1NN=C2>>[CH3:29][C:30]1[CH:31]=[C:32]([CH2:39][C@@H:40]([NH:44][C:45]([N:47]2[CH2:48][CH2:49][CH:50]([N:53]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][C:54]3=[O:63])[CH2:51][CH2:52]2)=[O:46])[C:41]([NH:1][C@H:2]([C:15](=[O:28])[N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:42])[CH:33]=[C:34]2[C:38]=1[NH:37][N:36]=[CH:35]2
Reactant: Cc1cc(C[C@@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCN(c2ccncc2)CC1
Agent: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12

Procedure:
The title compound was prepared from (S)-tert-butyl 5-amino-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate and (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxamido)propanoic acid using the same procedure as described for tert-butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate. The title compound was obtained in 66% yield. MS (ESI) 850 (M+H) ; Rf=2.07.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:11]([CH3:21])=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[C:14]([CH3:16])[CH:15]=1>>[Cl:9][C:10]1[C:11]([CH3:21])=[C:12]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:19])=[O:18])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1noc(N)c1Br
Reactant: Cc1cc(Cl)c(C)c(S(=O)(=O)Cl)c1
Product: Cc1cc(Cl)c(C)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 71 %

Procedure:
3-Chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-chloro-2,5-dimethylbenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 148-150° C., yield 71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.O[C:30]1[C:38]2[N:37]=N[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[NH2:35][C:34]1[CH:33]=[CH:32][CH:31]=[CH:30][C:38]=1[NH:37][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Agent: Nc1ccccc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.8 %

Procedure:
6-(6,7-Dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (38.4 mg, 0.2 mmol), hydroxybenzotriazole (16.2 mg, 0.12 mmol), triethylamine (40.4 mg, 0.4 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 200 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (39.1 mg, 84%) as a brown solid. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 4.97 (s, 2H, benzene-NH2), 6.65 (t, J=7.2 Hz, 1H, Ar—H), 6.82 (d, J=7.0 Hz, 1H, Ar—H), 7.00 (t, J=7.1 Hz, 1H, Ar—H), 7.38 (d, J=7.1 Hz, 1H, Ar—H), 7.42 (s, 1H, Ar—H), 7.60 (dd, J=2.4 and 9.2 Hz, 1H, Ar—H), 7.64-7.68 (m, 2H, Ar—H), 7.87 (d, J=6.7 Hz, 1H, Ar—H), 7.97 (d, J=2.3 Hz, 1H, Ar—H), 8.09 (d, J=8.2 Hz, 1H, Ar—H), 8.38 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.85 (s, 1H, benzene-NH). LC-MS (m/z) 467 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].[Cl-].[Na+]>CN(C)C=O.O>[C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)(=[O:40])[CH3:39]
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 528 mg (1.25 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 15 ml of dimethylformamide were added 0.57 ml (4.09 mmol) of triethylamine and 0.31 ml (3.29 mmol) of acetic anhydride, followed by overnight stirring at room temperature in an atmosphere of argon. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals; were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH2:33][OH:34])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH:33]=[O:34])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 110.7 %

Procedure:
A solution of methylene chloride (80 ml) and dimethyl sulfoxide (2.98 ml, 40 mmol) was cooled to -78° C., and oxalyl chloride (1.85 ml, 21.2 mmol) was dropwise added thereto. The mixture was stirred for 15 minutes at the same temperature, and then a solution of (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(3-hydroxypropyl)pyrrolidine (5 g, 13.9 mmol) in methylene chloride (70 ml) was dropwise added thereto over a period of 10 minutes. The mixture was stirred for 30 minutes, and then triethylamine (9.66 ml, 69.3 mmol) was added thereto. The mixture was heated to room temperature and stirred for 15 minutes. The reaction solution was concentrated in vacuo, and ethyl acetate (70 ml) was added thereto. The mixture was washed twice with 10% aqueous citric acid (30 ml) and further with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to obtain (2R,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-formylethyl)pyrrolidine (5.5 g, yield: 100%) as crude product. This compound was used for the subsequent reaction without purification.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)Cl.[CH3:13][N:14]1[C:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[S:21][C:17]=2[C:16]([NH2:26])=[N:15]1>N1C=CC=CC=1>[ClH:9].[CH3:13][N:14]1[C:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[S:21][C:17]=2[C:16]([NH:26][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[N:15]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cn1nc(N)c2sc3ccccc3c21
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cl
Product: Cn1nc(NC(=O)c2cccnc2)c2sc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 14.2 g. of nicotinic acid chloride in 100 ml. of methylene chloride was added to a stirred solution of 0.1 mole of 1-methyl-1H-(1)benzothieno-[3,2-c]pyrazol-3-amine in 400 ml. of methylene chloride containing 10 ml. of pyridine. The reaction mixture was stirred overnight at room temperature and the precipitate which formed was collected by filtration. Recrystallization from glacial acetic acid/concentrated hydrochloric acid gave N-(1-methyl-1H-(1)benzothieno[3,2-c]pyrazol-3-yl)-3-pyridinecarboxamide hydrochloride, m.p. 298°-300° C.
Reaction SMILES: [Cl-].[CH2:2]1[N+:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[F:10][C:11]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:34])[NH:15]2.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OC)(C)(C)C>[F:10][C:11]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:4][CH2:3][CH2:2][N:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:34])[NH:15]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: C1CC[N+]2(C1)CCC2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCCC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
4-Azoniaspiro[3,4]octane chloride (1.14 g) was added to a mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol (2.5 g), 1-methyl-2-pyrrolidinone (25 ml), methyl tert-butyl ether (1.8 ml) and potassium carbonate (815 mg) at 80° C. After stirring at 80° C. for 3 hours water (27 ml) was added over 40 minutes. The mixture was allowed to cool to 20° C. and left overnight. The mixture was reheated to 60° C. and filtered. The filter cake was washed with 1:1 v/v 1-methyl-2-pyrrolidinone/water (5 ml) and then with water (4×5 ml). The solid was dried in a vacuum oven to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[N+:18]([C:17]1[C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
5-Aminoindole (0.264 g, 2.00 mmoles) and 2-chloro-3-nitropyridine (0.476 g, 3.00 mmoles) were combined with triethylamine (0.42 ml, 3.01 mmoles) in absolute ethanol. The reaction was heated at room temperature under nitrogen for 72 hours. The resulting reaction mixture was filtered to afford the title compound (69%) as a dark red solid. Mp, 162.0°-163.5° C.; Rf =0.6 in diethyl ether; 13C NMR (DMSO-d6) δ155.6, 150.5, 135.5, 133.5, 129.7, 127.9, 127.6, 125.9, 118.5, 115.0, 113.4, 111.2, 101.2. Analytical calculated for C13H10N4O2 : C, 61.41; H, 3.96; N, 22.04. Found: 61.22; H, 3.80; N, 22.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([O:70][C:71]([CH:73]1[CH2:77][CH2:76][CH2:75][NH:74]1)=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]1[CH2:75][CH2:76][CH2:77][CH:73]1[C:71]([O:70][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:72])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OCc1ccccc1)C1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3C(=O)OCc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-benzyloxycarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:9][C:10]1([CH2:21][OH:22])[O:14][C:13]2=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]2[CH2:11]1.[H-].[Na+].C(=O)=O.CC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:21][C:10]2([CH3:9])[O:14][C:13]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:12]3[CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
5-Bromo-2-fluoropyridine (91) (0.25 mL, 2.43 mmol) was added to a solution of alcohol 101 (200 mg, 1.01 mmol) in anhydrous DMF (4.5 mL) under N2 at 0° C. The resulting mixture was treated with 60% NaH (64 mg, 1.60 mmol), then quickly degassed and resealed under N2. Further 5-bromo-2-fluoropyridine (91) (0.25 mL, 2.43 mmol) was added and the mixture was stirred at room temperature for 2 h, and then cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (15 mL), added to brine (40 mL) and extracted with CH2Cl2 (8×40 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 0-1.5% EtOAc/CH2Cl2 gave 2-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (102) (130 mg, 36%) as a cream solid: mp (CH2Cl2/hexane) 151-153° C.; 1H NMR (CDCl3) δ 8.17 (dd, J=2.5, 0.5 Hz, 1H), 7.68 (dd, J=8.8, 2.5 Hz, 1H), 7.52 (s, 1H), 6.60 (dd, J=8.7, 0.6 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.41 (d, J=10.2 Hz, 1H), 4.01 (d, J=10.2 Hz, 1H), 1.76 (s, 3H). Anal. (C12H11BrN4O4) C, H, N.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([O:10]C(C)(C)C)=[O:9].Cl>>[O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:8]([OH:10])=[O:9]
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1CCCS1(=O)=O
Agent: Cl
Product: CC(C)C[C@@H](C(=O)O)N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl(2S)-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methylpentanoate (0.656 g, 2.251 mmol) from Step B was combined with HCl (4 N in dioxane, 5 mL, 20.00 mmol). The reaction mixture was stirred at room temperature for 24 hours, then the solvent removed in vacuo to furnish (2S)-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methylpentanoic acid: MS (DCI+) m/z 253 (M+NH4)+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CN1CCCC1=O>CO>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([N:27]5[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]5)=[CH:35][CH:34]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Temperature: 150 °C

Procedure:
Into a 30 mL vial, 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (80 mg, 0.0002 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.100 g, 0.000525 mol) and N-Methylpyrrolidinone (0.25 mL, 0.0026 mol) were added. The reaction mixture was heated at 150° C. for 90 minutes. The reaction was cool to room temperature. Methanol (15 mL) was added. The solid was filtered and washed with hot MeOH (10 mL) to afford [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a light brown solid. MP 234-238° C. LCMS (E/I+) 373.18 (M+H). NMR 1H (DSMO-d6)-9.31 (s, 1H), 9.00 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.02 (d, 2H, J=8.16 Hz), 7.57 (d, 2H, J=8.79 Hz), 7.33 (d, 1H, J=4.77 Hz), 6.95 (d, 1H, J=4.76 Hz), 6.95-7.04 (m, 3H), 3.28 (s, 3H), 3.09 (bs, 4H), 2.40-2.56 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: C=C1[CH:7]2[CH:5]3[CH:6]2CC1[CH:4]3[C:9]1[NH:17][C:16]2[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=2[N:10]=1.C[N+]1([O-])CC[O:30][CH2:29]C1.[CH3:34][C:35]([CH3:37])=[O:36].O>O=[Os](=O)(=O)=O>[OH:36][C:35]1([CH2:29][OH:30])[CH:37]2[CH:5]3[CH:6]2[CH2:7][CH:34]1[CH:4]3[C:9]1[NH:17][C:16]2[C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH3:21])[C:13](=[O:22])[N:12]([CH2:23][CH2:24][CH3:25])[C:11]=2[N:10]=1
Reactant: C=C1C2CC3C1C3C2c1nc2c([nH]1)c(=O)n(CCC)c(=O)n2CCC
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C3C4C5CC3C(O)(CO)C54)nc2n(CCC)c1=O
Reaction time: 0.25 h

Procedure:
8-(5-Methylene-tricyclo[2.2.1.02,6]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (284 mg) was taken in acetone:water (1:1, 5 ml) at 0° C. OsO4 (2 ml) was added and the mixture was stirred for 15 min. N-Methylmorpholine-N-oxide (120 mg) was added and the mixture was stirred at room temperature overnight. The next day the reaction mixture was quenched with NaHSO3 solution, extracted with ethyl acetate (3×25 ml). Combined organic layer was washed with water, brine and dried over Na2SO4. After concentration the crude product was purified on a silica column. (ES+ 375)
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:12][CH2:13][C@H:14]([OH:16])[CH3:15].Cl.NCC(N)=O>>[OH:16][C@H:14]([CH3:15])[CH2:13][NH:12][C:9]([C@@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: C[C@@H](O)CN
Reactant: O=C(O)C1CC12CCCCC2
Agent: Cl
Agent: NCC(N)=O
Product: C[C@@H](O)CNC(=O)[C@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 6 for the product from Example 1B and substituting (R)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 173.9, 67.5, 48.0, 38.7, 30.2, 30.0, 28.9, 27.5, 26.9, 26.8, 21.1, 19.4; MS (CI) m/z 212 (M+H)+.
Reaction SMILES: N[C@@H](CCC(N[C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=O)[CH2:12]S)=O)C(O)=O.N1CCC[C@H]1C(O)=[O:24].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>>[NH:16]1[CH2:14][C@H:11]([OH:24])[CH2:12][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 37 °C
Reaction time: 8 h

Procedure:
A plasmid (pGST-CM4, FIG. 60) containing the gene for collagen mimetic 4 (CM4, FIG. 61) (SEQ. ID. NO. 39) genetically linked to the 3′ end of the gene for S. japonicum glutathione S-transferase was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 100 μg/ml ampicillin. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 5 ml of LB media containing 100 μg/ml ampicillin. After overnight growth at 37° C., 500 μl of this culture was centrifuged, the supernatent discarded, and the cell pellet washed once with 500 μl 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 400 μg/ml ampicillin). The cells were finally suspended in 5 ml of M9 medium containing 10 μm/ml proline and 2 ml of this was used to inoculate 30 ml of M9 medium containing 10 μg/ml proline. After incubation with shaking at 37° C. for 8 hours, the culture was centrifuged and the cell pellet washed once with M9 medium containing 5 μg/ml proline. The pellet was resuspended in 15 ml of M9 medium containing 5 μg/ml of proline and this culture was used to inoculate 1 L of M9 medium containing 5 μg/ml of proline. This culture was grown for 18 hours at 37° C. to proline starvation. At this time, the culture was centrifuged, the cells washed once with M9 medium (with no proline), and the cells resuspended in 1 L of M9 medium containing 80 mM hydroxyproline, 0.5M NaCl, and 1.5 mM isopropyl-β-D-thiogalactopyranoside. Incubation was continued at 37° C. with shaking for 22 hours. The cultures were centrifuged and the cell pellets stored at −20° C. until processed further.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[CH2:4][N:5]([CH2:13][C:14]([NH:16][CH3:17])=[O:15])CC1C=CC=CC=1>CO.[Pd]>[CH3:17][NH:16][C:14](=[O:15])[CH2:13][NH:5][CH2:4][C:3]([NH:2][CH3:1])=[O:18]
Reactant: CNC(=O)CN(CC(=O)NC)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)CNCC(=O)NC
Temperature: 40 °C

Procedure:
The mixture of N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide (3.09 g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15 g). The mixture was stirred and heated to 40° C. under 40 psi H2 for 10 h, filtered and concentrated in vacuo to yield N-(2-methylamino-2-oxoethyl)-glycine methylamide in quantitative yield (1.76 g). 1H NMR (CDCl3): δ 6.95(br s, 2H), 3.23 (s, 4H), 2.79 (d, J=6.0, 4.8 Hz), 2.25(br s 1H); MS (ESI) m/e 160(M+H+)