Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:22][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: CCN1CCc2sc3ncn(CCO)c(=O)c3c2C1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCN1CCc2sc3ncn(CCCl)c(=O)c3c2C1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
10.5 g (37.6 mmol) of 3-(2-hydroxyethyl)-6-ethyl-3,4,5,6,7,8-hexahydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-one in 100 ml of 1,2-dichloroethane were heated to reflux (slow dissolution), after which 3.5 ml (48 mmol) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After 1 h of reflux boiling, the reaction mixture was allowed to cool down and the solid was filtered off with suction; it was then rewashed with 1,2-dichloroethane. The crude product was partitioned between methylene chloride and water at pH=9. After the organic phase had been dried and concentrated, 9.3 g (83%) of product were isolated as a dark oil, which slowly crystallizes throughout and which is sufficiently pure for the subsequent reactions, m.p. 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1ccc(Cl)cc1
Product: C[C@@H](CCl)COc1ccc(Cl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35]C(OC(C)(C)C)=O)[C:18]1=[O:19])(=[O:10])[CH3:9]>ClCCl>[C:8]([O:11][C@H:12]([CH3:43])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH3:28])[CH:23]=[N:22][C:21]=2[N:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:18]1=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCNC(=O)OC(C)(C)C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCN)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of (R)-1-(5-acetoxyhexyl)-3-(N-t-butyloxycarbonyl-6-aminohexyl)-7-methylxanthine (1.37 g) in dichloromethane (30 ml). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (20 ml), with water (20 ml), with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine (1.073 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:24])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C@H:8]([OH:13])[C@@H:7]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH:25]([CH:27]=O)=O.C(OCC)(=O)C>C(O)C>[CH3:12][C:9]1([CH3:11])[O:10][C:5]2[CH:4]=[C:3]3[C:2](=[CH:23][C:6]=2[C@H:7]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:8]1[OH:13])[N:1]=[CH:27][CH:25]=[N:24]3
Reactant: O=CC=O
Reactant: CC1(C)Oc2cc(N)c(N)cc2[C@H](NCCc2ccccc2)[C@H]1O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)Oc2cc3nccnc3cc2[C@H](NCCc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of (3R*,4S*)-6,7-diamino-3,4-dihydro-2,2-dimethyl-4-(2-phenylethylamino)-2H-benzopyran-3-ol (1.5 g, 4.58 mmol) in ethanol (30 mL), 40% aqueous glyoxal solution (997 mg, 6.87 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. Upon the completion of the reaction, ethyl acetate was added thereto, the resulting solution was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated sodium chloride solution, and then dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/1) to obtain the aimed product (yield: 74%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]([CH3:39])[C:22]1=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:7][C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]([CH3:39])[C:22]1=[O:40])=[O:19])([CH3:5])[CH3:6]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CN1C(=O)C(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21

Procedure:
The procedure of Example 77 was carried out in which Boc-D-phenylalanine was coupled to 3(R,S)-amino- 1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one using dicyclohexylcarbodiimide. Following the identical work-up and purification procedure of Example 77 gave the analytical product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:31]=[C:18]4[C:19]([C:23]5[CH:28]=[CH:27][C:26](F)=[C:25]([F:30])[CH:24]=5)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[O-:32][CH2:33][CH3:34].[Na+]>CCO>[CH2:33]([O:32][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[C:18]3[N:17]([N:16]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[CH:2][CH:7]=5)[CH2:13][CH2:12]4)[N:31]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:24][C:25]=1[F:30])[CH3:34]
Reactant: CC[O-]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)cc1F
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(-c2cccn3nc(NC4CCN(c5ccncc5)CC4)nc23)cc1F
Temperature: 150 °C

Procedure:
To a solution of N-(1-(2-chloropyridin-4-yl)piperidin-4-yl)-8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 169c) (88 mg, 0.20 mmol) in EtOH (1 mL) was added sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) and the reaction mixture was heated in the microwave to 150° C. for 30 minutes and then sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) was added and the resulting mixture heated to 150° C. for another 30 minutes. The mixture was then evaporated.
Reaction SMILES: C([NH:4][C@H:5]([C:12]([OH:14])=[O:13])[CH2:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1)(=O)C.[ClH:15]>>[ClH:15].[ClH:15].[S:10]1[CH:11]=[C:7]([CH2:6][C@@H:5]([C:12]([OH:14])=[O:13])[NH2:4])[N:8]=[CH:9]1
Reactant: CC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: Cl
Product: N[C@@H](Cc1cscn1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2 L round bottom flask equipped with a magnetic stirrer was charged with N-acetyl-3-(4-thiazolyl)-L-alanine from Example 1L (92.6 g, 0.43 mol) and 6M hydrochloric acid (1 L). The resultant solution was heated to reflux. After 3 hours the mixture was allowed to cool to ambient temperature. The solution was then concentrated under reduced pressure, evaporated from toluene (3×200 mL), and dried under vacuum overnight to give 120 g of a slightly wet solid. This material was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=O)=[CH:4][CH:3]=1.[ClH:12].Cl.[NH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:27]=2[CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1)(=[O:20])=[O:19].CCN(CC)CC.[BH4-].[Na+]>CO>[ClH:1].[ClH:12].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][C:27]=3[CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: O=CCOc1ccc(Cl)cc1
Reactant: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCNCCOc1ccc(Cl)cc1)c1cc(-c2ccccc2)cc2cnccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A 1.96 mL of (4-chloro-phenoxy)-acetaldehyde stock solution (˜0.46 mmol) is added to a stirred mixture of 7-phenyl-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide di-hydrochloride (152 mg, 0.380 mmol), 4 Å molecular sieve (300 mg) and NEt3 (0.212 mL, 1.52 mmol) in anhydrous CH3OH (4 mL) at ambient temperature under nitrogen. The resultant mixture is stirred for 16 hours. Then the mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (43.1 mg, 1.14 mmol). The mixture is stirred at 0° C. for 1 hour, then at ambient temperature for another 1 hour. After filtration and subsequent concentration in vacuo, the crude product is chromatographed on silica (gradient 5-25% CH3OH in EtOAc) to give 104 mg of the free amine product as a gum (0.216 mmol, 57% yield). The free amine (102 mg, 0.212 mmol) is dissolved in EtOAc (15 mL) and treated dropwise with 1N HCl/Et2O solution (0.635 mL) with stirring under nitrogen. The white suspension is stirred for 15 minutes, filtered and dried under vacuum at 60° C. to give 112 mg (0.202 mmol, 95% yield) of the title compound as a white powder. ESIMS: m/z 482 [(M+H)+, 35Cl], 484 [(M+H)+, 37Cl].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][C@H:29]([N:31]([CH3:36])[C:32](=[O:35])[CH2:33][OH:34])[CH3:30])[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[OH:15]>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][C@H:29]([N:31]([CH3:36])[C:32](=[O:35])[CH2:33][OH:34])[CH3:30])[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1
Reactant: C[C@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Reactant: ClCc1cscn1
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 64 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[(1R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide (obtained as described in Example 54, preparation of starting materials) to give the title compound as a white solid in 64% yield; NMR spectrum (DMSO-d6 373K) 1.25 (d, 3H), 2.83 (s, 3H), 3.98 (s, 2H), 4.34 (m, 1H), 4.47 (t, 1H), 4.98 (m, 1H), 5.34 (s, 2H), 7.19 (d, 1H), 7.37 (d, 2H), 7.51 (dd, 1H), 7.70 (t, 1H), 7.74 (d, 1H), 7.93 (d, 1H), 8.46 (s, 1H), 9.08 (s, 1H), 9.57 (s, 1H); Mass spectrum MH+ 514.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2 diethylamino-ethyl) amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl-]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide (86.2 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([O:8][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:7]=1
Reactant: BrCC1CCCC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCC3)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless powder (41%). MS (Turbo Spray): m/z=459.2 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:17])([CH3:16])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][CH:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:16])([CH3:17])[N:7]([C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NNC(C)(C)C1c1ccccc1
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC1=NN(C(=O)CC(C)CC(C)(C)C)C(C)(C)C1c1ccccc1
Temperature: 30 °C
Reaction time: 21 h
Yield: 57 %

Procedure:
To a magnetically stirred solution of 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole (1 ml: 0.25 M in anhydrous tetrahydrofuran, 0.25 mmol) was successively added 3,5,5-trimethylhexanoyl chloride (1.1 ml: 0.25 M in anhydrous tetrahydrofuran; 0.275 mmol) and DIPEA (1.1 ml: 0.285 M in anhydrous tetrahydrofuran; 0.313 mmol) and the resulting mixture was stirred for 21 hours at 30° C. An aqueous 5% NaHCO3 solution and dichloromethane were added to the mixture. The organic layer was separated, successively washed with brine and water, dried over MgSO4, filtered and concentrated in vacuo to give [3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazol-1-yl]-3,5,5-trimethylhexan-1-one as a mixture of diastereomers (55 mg, 57% yield). 1H-NMR (400 MHz, CDCl3) δ 0.88 (t, J=7, 3H), 0.94 (s, 9H), 1.00 and 1.01 (2×d, J=7, 3H), 1.12-1.20 (m, 4H), 1.25-1.39 (m, 3H), 1.47-1.58 (m, 5H), 2.07-2.34 (m, 3H), 2.46-2.55 (m, 1H), 2.63-2.73 (m, 1H), 3.72 and 3.74 (2×s, 1H), 6.98 (br d, J=8 Hz, 2H), 7.28-7.37 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1cc(F)cc(F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cc(F)cc(F)c2)cc1-c1c(Br)cnn1C
Yield: 81.8 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.59 (ttt, J=2.3, 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:43])(=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:31]=5)[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:38]([NH:37][S:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]2[N:23]3[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][CH:16]=4)=[N:22]3)=[CH:27][CH:28]=2)[CH:31]=1)(=[O:43])=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nn23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCNCC5)cc4)nn23)c1
Yield: 95.8 %

Procedure:
4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (50.0 mg, 0.0827 mmol) was treated with trifluoroacetic acid (191 uL, 2.48 mmol) in methylene chloride (3.00 mL). The reaction was diluted with DCM (25 mL) and washed with saturated sodium bicarbonate (25 mL). The aqueous layer was extracted with DCM (25 mL) three times and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as an orange foam (40 mg, 96%). LCMS (m/e) 505 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H), 8.73 (s, 1H), 8.29 (d, 1H, J=7.8 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.62-7.51 (m, 3H), 7.28 (d, 2H, J=8.3 Hz), 7.07 (d, 1H, J=4.8 Hz), 6.92 (bs, 1H), 6.84 (d, 1H, J=4.8 Hz), 4.77-4.57 (m, 1H), 3.01-3.20 (m, 2H), 2.87-2.73 (m, 2H), 2.72-2.59 (m, 1H), 1.94-1.82 (m, 2H), 1.79-1.63 (m, 2H), 1.17 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:2].OO.[ClH:21]>>[C:1]([C:3]1[CH:18]=[C:17]([Cl:21])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10]([CH3:11])([CH3:12])[CH3:13])#[N:2]
Reactant: CC(C)(C)NCC(O)COc1ccccc1C#N
Reactant: Cl
Agent: OO
Product: CC(C)(C)NCC(O)COc1ccc(Cl)cc1C#N
Temperature: 45 °C

Procedure:
5.7 gm (0.02 mol) of 1-(2-cyanophenoxy)-2-hydroxy-3-tert.-butylamino propane (prepared analogous to Example II) were dissolved in 32 ml of concentrated HCl and while stirring at 45° C. 2.27 gm of 35% hydrogen peroxide were added drowise so that the temperature did not exceed 65° C. Thereafter, the temperature was maintained at 60° C. for 30 minutes and the mixture was concentrated in vacuo at the end of which a solid residue remained. The raw hydrochloride was recrystallized from ethanol under an addition of ether to obtain 3 gm of 1-(2-cyano-4-chloro-phenoxy)-2-hydroxy-3-tert.-butylamino propane hydrochloric having a melting point of 180°-182° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(F)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(F)cc2)cc1

Procedure:
49.7 mg of solid beige-coloured 3-{4-[3-(4-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-fluorophenyl isocyanate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=5)[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: OCc1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(-c5nc(CO)cs5)sc34)ccc12

Procedure:
This material was prepared by the reaction of [2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-methanol with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methyl amide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (1H, d, J=5.5 Hz), 8.14 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.63 (1H, s), 7.58 (1H, d, J=4.7 Hz), 7.54 (1H, d, J=2.0 Hz), 7.04 (1H, dd, J=2.0, 8.6 Hz), 6.64 (1H, d, J=5.5 Hz), 4.60 (2H, s), 3.67 (3H, s), 2.80 (3H, d, J=4.3 Hz), 2.61 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 465. found 465. Anal. (C23H20N4O3S2.0.6CH3OH) C, H, N.
Reaction SMILES: [CH3:1][NH:2][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[C:27]1([CH2:33][O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][N:2]([C:39](=[O:40])[CH2:38][NH:37][C:35]([O:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:36])[C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CNC1(C(=O)OC)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C1(N(C)C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of methyl 1-(methylamino)cyclopropanecarboxylate (1.53 g, 11.85 mmol) and HOBt (1.920 g, 14.21 mmol) in CH2Cl2 (30 mL) was added 4-methylmorpholine (5.2 mL, 47.40 mmol), N-{[(phenylmethyl)oxy]carbonyl}glycine (2.48 g, 11.85 mmol), and EDCI (2.73 g, 14.21 mmol). After stirring overnight, the solution was washed 6 N aq. HCl (100 mL) and water (100 mL). The aqueous layers were extracted with CH2Cl2 (1×100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over anhydrous MgSO4 and concentrated in vacuo to provide pure methyl 1-[methyl(N-{[(phenylmethyl)oxy]carbonyl}glycyl)amino]cyclopropanecarboxylate (3.66 g, 97%). LCMS: (M+H)+: 321.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])[C:5]2=[O:20].[P:21](O)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][O:19][P:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])=[O:15])[C:5]2=[O:20]
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Reactant: CCn1cc(C(=O)OCCO)c(=O)c2cc(Br)cnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1cc(C(=O)OCCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
2-Hydroxyethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 23, 100 mg, 0.29 mol), dibenzyl hydrogen phosphate (65 mg, 0.23 mmol) and triphenylphosphine (192 mg, 0.733 mmol) were dissolved in tetrahydrofuran (15 mL). Diisopropyl azodicarboxylate [DIAD] (106 mg, 0.52 mmol) was added drop wise and the mixture was stirred for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure and water (100 mL) was added. The aqueous mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a crude compound. The crude compound was purified by flash column chromatography over silica gel (10-50% ethyl acetate/petroleum ether) to afford 60 mg (40%) of 2-{[bis(benzyloxy)phosphoryl]oxy}ethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.