Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[CH2:7]([O:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:11])[CH3:8].[C:21]([NH:24][C@@H:25]1[C@@H:30]([O:31]C(=O)C)[C@H:29]([O:35]C(=O)C)[C@@H:28]([CH2:39][O:40]C(=O)C)[O:27][C@@H:26]1Cl)(=[O:23])[CH3:22].O.NN>C1C=CC=CC=1.ClCCl>[C:21]([NH:24][C@@H:25]1[C@@H:30]([OH:31])[C@H:29]([OH:35])[C@@H:28]([CH2:39][OH:40])[O:27][C@H:26]1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])(=[O:23])[CH3:22]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Reactant: CCOC(=O)CCCCCCCCO
Agent: NN
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mercuric cyanide (31.8 g, 126 mmol) and anhydrous calcium sulfate were added to a solution of 8-ethoxycarbonyl-1-octanol (25 g, 124 mmol) in 100 ml of dry benzene. The mixture was protected from moisture while stirring for 1 h at room temperature prior to addition of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride (25 g, 68 mmol). The mixture was efficiently stirred for 4 days at room temperature. Dichloromethane (400 ml) was added, the solids were removed by filtration, and the filtrate was sequentially washed with 10% aqueous sodium chloride solution (50 ml), once with saturated aqueous sodium bicarbonate solution (25 ml), and twice with water (50 ml). In each case, the aqueous layer was back-extracted with a little dichloromethane. After drying over magnesium sulfate, the solvents were removed to leave a syrup which crystallized from a mixture of diethyl ether and n-hexane. The crude yield of 8-ethoxycarbonyloctyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranoside was 28.9 g (80%). A recrystallized sample showed mp 112°, [α]D20 -12.2° (c 2.4, chloroform). De-O-acetylation of this compound with triethylamine (27 ml) in methanol (500 ml) at 0°-5° for 18 h gave after evaporation of the solvent compound 2 as a chromatographically homogeneous powder which resisted crystallization and was therefore characterized as its hydrazide derivative mp 200°-201°, [α]D26 -22.5° (c 1, water), prepared by treating 2 with an 85% solution of hydrazine hydrate.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:13]([CH2:21][CH3:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:12]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]([CH2:21][CH3:22])[CH2:11][CH3:12])=[CH:19][CH:18]=1
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: Clc1nc2ccccc2s1
Product: CCN(CC)c1ccc(Nc2nc3ccccc3s2)cc1

Procedure:
The title compound was synthesised from 2-Chloro-benzothiazole (commercially available) and N,N-Diethyl-p-phenylenediamine (commercially available) according to the procedure described for Example 1a) above. MS (m/e): 298.2 (MH+, 100%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:18]2[C:19]([Cl:23])=[N:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[CH2:29][CH3:30])(=O)C.O>CN(C)C=O>[CH2:7]([N:14]1[C:18]2[C:19]([Cl:23])=[N:20][CH:21]=[CH:22][C:17]=2[N:16]([CH2:15][C:30]2[CH:29]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]#[N:14])[C:1]1=[O:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: O=c1[nH]c2ccnc(Cl)c2n1Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Cn1c(=O)n(Cc2ccccc2)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (0.152 g) and (2-bromomethyl)benzonitrile (0.216 g) were added to a solution of 3-benzyl-4-chloro1,3-dihydroimidazo[4.5-c]pyridin-2-one (0.259 g) in N,N-dimethylformamide (5 mL). This was stirred at room temperature for 16 hours. Ethyl acetate (60 mL) and water (30 mL) were added, and the organic layer was washed twice with 30 mL of water and once with 30 mL of saturated aqueous sodium chloride solution. This was then dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure, and the residue was then purified by silica gel chromatography. The ethyl acetate:hexane 3:2 fraction gave the title compound (0.364 g).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][N:6]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH2:23][C@H:24]([OH:37])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:26]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.O.[OH-].[Li+].C(O)(=O)C>C(O)C.O>[CH:39]1([CH2:38][N:6]([CH2:5][C:4]([OH:42])=[O:3])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][CH:19]([NH:22][CH2:23][C@H:24]([OH:37])[C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:26]=4)[CH2:20][CH2:21]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:41][CH2:40]1
Reactant: CCOC(=O)CN(CC1CC1)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N(CC(=O)O)CC4CC4)cc3)CC2)ccc1O
Reaction time: 0.33 h

Procedure:
To a stirred solution of 0.15 9 (0.24 mmol) of [cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic acid ethyl ester ( ) in 2 mL of ethanol, 0.1 g (2.4 mmol) of lithium hydroxide monohydrate in 2 ml of water was added dropwise over 10 minutes. After 20 minutes, the reaction mixture was quenched with .13 ml (2.4 mmol) of glacial acetic acid. The solvent was removed in vacuo and the pink aqueous residue was pipetted out of the flask. The solid was then washed with water and ethyl acetate and then dried via vacuum line to give 0.134 g of the title compound as a tan solid; 1H NMR (DMSO) δ 0.82 (m, 1H), 1.41 (m, 2H), 1.85-1.97 (m, 2H), 2.68-2.82 (m, 8H), 2.92 (s, 3H), 3.04 (d, J=6.84 Hz, 2H), 3.30 (m, 5H), 3.76 (m, 4H), 4.58 (m, 1H), 6.83 (d, J=8.25 Hz, 1H), 6.94-7.05 (m, 3H), 7.18 (d, J=1.86 Hz, 1H), 7.60 (d, J=8.88 Hz, 2H); MS (ES) m/z 597.1 (MH+); HRMS (MH−) for C26H36N4O8S2: 595.1904.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[O:10])=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19].[CH2:20](O)C>>[CH3:17][N:18]([CH3:20])[CH2:19][CH:9]([OH:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCO
Reactant: CNC
Reactant: O=CC(c1ccccc1)c1ccc(Cl)cc1
Product: CN(C)CC(O)C(c1ccccc1)c1ccc(Cl)cc1
Yield: 37 %

Procedure:
p-Chlorophenyl-phenylacetaldehyde (5.68 g.) was reacted with dimethylsulphoxonium methylide and the crude epoxide obtained further reacted with dimethylamine in ethanol by the procedures described in Example 8 to give 3-dimethylamino-1-p-chlorophenyl-1-phenyl-propan-2-ol (2.6g., 37% from aldehyde) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14])[CH3:2]
Reactant: CCOC(=O)CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1C(=O)c2ccccc2C1=O
Yield: 43.7 %

Procedure:
This compound was prepared according to the procedure used to prepare 1,3-dihydro-1,3-dioxo-2H-isoindoleoctanoic acid ethyl ester. Thus, a mixture of 100.0 g (0.55 mole) of 3-bromopropionic acid ethyl ester (99%, Aldrich) and 108.7 g (0.58 mole) of potassium phthalimide (98%, Aldrich) in 300 mL of dimethylformamide gave 59.4 g (44%) of crude title compound as an oily residue. A 3.0 g sample of this oil was purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:10). Fractions containing title compound were combined and the solvents evaporated under reduced pressure to give 2.3 g (77% recovery) of a pale-yellow oil.
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[CH:35]=[C:36]([CH3:39])[C:37]=1[OH:38].[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4OC5C=CC=C(C)C=5N=4)=[CH:53][CH:52]=3)[C:43]=12>>[NH2:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C@H:68]3[CH2:73][CH2:72][C@@H:71]([N:74]4[CH2:75][CH2:76][N:77]([CH3:80])[CH2:78][CH2:79]4)[CH2:70][CH2:69]3)[N:49]=[C:50]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]4[O:38][C:37]5[C:36]([CH3:39])=[CH:35][C:34]([CH3:40])=[CH:33][C:32]=5[N:31]=4)=[CH:53][CH:52]=3)[C:43]=12
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Reactant: Cc1cc(C)c(O)c(N)c1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.246 mmol) and 6-amino-2,4-xylenol (0.034 g, 0.246 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.031 g, 23%): 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.23 (s, 1H), 7.93 (d, 2H), 7.65 (d, 2H), 7.11 (s, 1H), 6.80 (s, 1H), 4.80 (m, 1H), 2.60-2.17 (m, 12H), 2.41 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H), 1.71-1.59 (m, 5H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=8.00 min., 93%; m/z 552 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[N:8]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])[CH:9]=[CH:10][CH:11]=1.[C:21](=O)([O-])[O-:22].[Na+].[Na+]>CN(C=O)C>[Br:6][C:7]1[N:8]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])[C:9]([CH:21]=[O:22])=[CH:10][CH:11]=1
Reactant: Cc1cc(C#N)ccc1-n1cccc1Br
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C#N)ccc1-n1c(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
DMF (0.1 mL) was added to phosphorus oxychloride (0.5 mL, 5.2 mmol) at 0° C., and the mixture was stirred at room temperature for 1.5 h. At 0° C., a solution of compound 50B (100 mg. 0.36 mmol) in DMF (2 mL) was added, and the resultant mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice-water, adjusted to pH=8 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to afford 50C (60 mg, yield 58%).
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]([C:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]=1[C:41]1[CH:50]=[CH:49][C:48]([OH:51])=[C:47]2[C:42]=1[CH:43]=[CH:44][CH:45]=[N:46]2)[CH2:28][CH2:29][CH2:30][CH3:31].Br[CH2:53][C:54]#[N:55]>>[CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]([C:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]=1[C:41]1[CH:50]=[CH:49][C:48]([O:51][CH2:53][C:54]#[N:55])=[C:47]2[C:42]=1[CH:43]=[CH:44][CH:45]=[N:46]2)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCc1c(-c2ccc(OC)c3ncccc23)oc2ccccc12
Reactant: N#CCBr
Agent: CCCCCc1c(-c2ccc(O)c3ncccc23)oc2ccccc12
Product: CCCCCc1c(-c2ccc(OCC#N)c3ncccc23)oc2ccccc12
Yield: 48 %

Procedure:
5-(3-Pentyl-1-benzofuran-2-yl)-8-hydroxy-quinoline was prepared as a solid (0.113 g, 99%) from 5-(3-pentyl-1-benzofuran-2-yl)-8-methoxy-quinoline according to the procedure described in the first part of Step 4 of Example 2. Mass spectrum (+ESI, [M+H)+) m/z 332. Reaction of 5-(3-Pentyl-1-benzofuran-2-yl)-8-hydroxy-quinoline with bromoacetonitrile according to the procedure described in Step 2 of Example 1 afforded the title compound as a solid (0.059 g, 48%). Mass spectrum (+ESI, [M+H)+) m/z 371. 1H NMR (500 MHz, DMSO-d6): δ 8.94-9.02 (m, 1H), 8.20 (d, 1H, J=9.5 Hz), 7.72-7.83 (m, 2H), 7.60-7.70 (m, 2H), 7.53 (d, 1H, J=8.6 Hz), 7.28-7.42 (m, 2H), 5.52 (s, 2H), 2.68 (t, 2H, J=7.4 Hz), 1.50-1.67 (m, 2H), 1.03-1.26 (m, 4H), and 0.67 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].B>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1sc2ccccc2c1Cl
Agent: B
Solvent: C1CCOC1
Product: OCc1sc2ccccc2c1Cl
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-benzo[b]thiophene-2-carboxylic acid (3.5 g, 16.6 mmol) in THF (40 mL) at 0° C. was added drop-wise 1 M borane in THF (33 mL, 33.2 mmol) via a dropping funnel. The mixture was stirred at r.t overnight. The reaction was quenched with drop-wise addition of water (6 mL). Solvent was evaporated in vacuo and the residue was partitioned between sat. sodium carbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate (100 mL), the combined organic phases was washed with water (3×100 mL), dried and concentrated to give (3-chloro-benzo[b]thiophen-2-yl)-methanol as a light yellow solid (3.4 g, 103% crude yield); 1H NMR (DMSO-d6) δ 4.8 (d, J=5.8 Hz, 2H, CH2OH), 5.87 (t, J=5.8 Hz, 1H, CH2OH), 7.42-8.04 (m, 4H, Ar). The product was used in the next step without further purification.
Reaction SMILES: C(OC(=O)C[C@@H](N1C=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.[CH2:43]([O:50][C:51](=[O:72])[CH2:52][C@@H:53]([NH:64][C:65](OC(C)(C)C)=O)[C:54]([NH:56][C@@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[OH:63])=[O:55])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1>C(O)(=O)C>[CH2:43]([O:50][C:51](=[O:72])[CH2:52][C@@H:53]([N:64]1[CH:65]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28]1)[C:54]([NH:56][C@@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[OH:63])=[O:55])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCCC[C@H]1O
Reactant: O=C(C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: CC(=O)O
Product: O=C(C[C@H](C(=O)N[C@@H]1CCCC[C@H]1O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Yield: 41 %

Procedure:
As described in Example 1(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(3-(biphenyl-4-yl)-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2(R)-hydroxycyclohex-1(R)-yl)succinamic acid benzyl ester and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in acetic acid to furnish in 41% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2(R)-hydroxycyclohex-1(R)-yl)succinamic acid benzyl ester as an amorphous off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[Br:17]Br>O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:17])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COC(=O)c1ncccc1N
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1nc(Br)ccc1N
Temperature: 0 °C
Yield: 50 %

Procedure:
20 g of methyl 3-aminopyridine-2-carboxylate are suspended in 120 ml of water in a flask. After addition of 100 ml of sulfuric acid (2 mol/l), the mixture is cooled to 0° C., 6.73 ml of bromine are added dropwise, and the mixture is stirred at 25° C. until the acid has reacted completely (HPLC check, about 24 hours). A precipitate precipitates out of the reaction solution. This is filtered off, dissolved in EA, washed with sodium thiosulfate solution, the organic phase is dried and purified by means of column chromatography (gradient heptane: EA 5-100% in 30 min.), giving 15 g of methyl 3-amino-6-bromo-pyridine-2-carboxylate as red-brown solid (yield 50%, content 98%); MS-FAB (M+H+)=232.9; Rf (polar method): 1.518 min.
Reaction SMILES: [N:1]#[N:2].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][C@H:17]([C:25]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14].O.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(O)C1C=CC=CC=1.C1C=CC=CC=1>[N:1]#[N:2].[C:37]1([CH3:47])[CH:38]=[CH:39][C:40]([S:43]([OH:46])(=[O:44])=[O:45])=[CH:41][CH:42]=1.[CH2:47]([O:30][C:29](=[O:31])[CH2:28][N:27]([C:25](=[O:26])[C@H:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])[NH:16][S:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)(=[O:14])=[O:15])[CH2:32][CH2:33][CH2:34][CH3:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: c1ccccc1
Solvent: O
Solvent: OCc1ccccc1
Product: CCCCN(CC(=O)OCc1ccccc1)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 94.9 %

Procedure:
A mixture of 1.2 g of N2 -(2-naphthalenesulfonyl)-L-arginyl-N-butylglycine and 1.0 g of p-toluenesulfonic acid monohydrate in 5 ml of benzyl alcohol and 30 ml of benzene was refluxed for 5 hours, while removing water by azeotropic distillation. At the end of this period, the solvent was evaporated and then 100 ml of ethyl ether was added to the residue to give 1.73 g (93%) of N2 -(2-naphthalenesulfonyl) L-arginyl-N-butylglycine benzyl ester p-toluenesulfonate in the form of a powder.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37](C)[CH:36]=C[C:34]=2F)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=C[N:52]=1>>[ClH:1].[ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[N:52][CH:34]=2)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1ccc(F)c(C(=O)Nc2ccc(Oc3ncnn4cc(C(=O)NCCN5CCOCC5)c(C)c34)c(F)c2)c1
Agent: Cl
Product: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12
Yield: 39 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 50, 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholinoethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (30 mg, 0.07 mmol, Compound C of Example 50) was converted the title compound (16 mg, 39%) as a 2.HCl salt. 1H NMR (CD3OD) δ 9.08 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.87 (m, 2H), 7.38 (m, 2H), 7.22 (m, 2H), 3.82 (s, 4H), 3.61 (m, 2H), 2.75 (m, 9H); MS(ESI+) m/z 520.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14].[O-]Cl.[Na+]>C(Cl)Cl.O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]#[N+:13][O-:14]
Reactant: O=C1NCCN1CCOc1ccccc1C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: O=C1NCCN1CCOc1ccccc1C#[N+][O-]
Temperature: -18 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 2-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde oxime (20.2 g, 0.081 mol) in CH2Cl2 (400 mL) at −1° C. is added, dropwise over 10 minutes, an aqueous NaOCl solution in water (157 mL, Aldrich, >4% of active chlorine). The reaction medium is then stirred for 20 minutes. The aqueous and organic phases are separated and the aqueous phase is extracted with CH2Cl2 (twice 75 mL). The combined organic phases are washed with water (3 times 10 mL) and dried over Na2SO4. The phases are concentrated to 100 mL under reduced pressure at room temperature. 50 mL of petroleum ether are added. The solution is cooled to −18° C. (3 hours). The precipitate is filtered, washed with CH2Cl2/petroleum ether (5 mL/10 mL; then 5 mL/20 mL; then 0 mL/20 mL) and then dried under atmospheric pressure at room temperature.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)[CH:34]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
276 mg (1.26 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 350 mg (0.987 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 350 mg (2.53 mmol) potassium carbonate in 2 mL NMP were stirred for 2 h at 130° C. After cooling to RT the reaction mixture was diluted with DMF and purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:22])[C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>O.CC(C)=O>[CH:23]1([NH:29][C:30]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[N:4]([CH3:22])[CH3:3])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN(C)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1
Temperature: 25 °C

Procedure:
8.8 Ml. of 2N sodium hydroxide are added while stirring at 25° C. to a mixture of 5.2 g. of 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide in 180 ml. of acetone, during which the solid material first dissolves and then a new crystalline precipitate immediately results. 2.26 Ml. of cyclohexylisocyanate are then added thereto while cooling externally with ice and stirring, whereupon the solid material passes completely into solution and then a crystalline precipitate soon reappears. The mixture is subsequently stirred for 16 hours at 25° C., then diluted with 350 ml. of water, acidified to pH 2 with 3N hydrochloric acid and finally extracted twice with 500 ml. of chloroform each time. The chloroform extracts are dried over sodium sulfate and evaporated in vacuo at 60° C. The residue is dissolved in 25 ml. of acetone and crystallized by trituration. There is obtained 1-cyclohexyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 113° C. (with decomposition).