Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:15]([C:13]2[S:14][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:17])=[O:16])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCc1ccncc1)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a stirred solution of 4-aminomethyl-pyridine (1.24 g, 11.5 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) dissolved in THF (8 ml) and triethylamine (0.59 ml, 4.21 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and crystallization from dichloromethane/hexane to yield the title compound (1.21 g, 95%) as a white solid. MS (ISN) 330.8 [(M−H)−], mp 159° C.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1>>[CH:1]1([NH:5][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 6 which is concerned with the preparation of starting material, cyclobutylamine was reacted with 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid to give N-cyclobutyl-4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZ12239932); NMR Spectrum: (CDCl3) 1.11 (d, 6H), 1.75 (m, 2H), 1.93 (m, 2H), 2.23 (s, 3H), 2.41 (m, 2H), 2.75 (m, 5H), 3.38 (m, 4H), 4.57 (m, 1H), 6.30 (d, 1H), 7.26 (s, 1H), 7.44 (m, 2H), 7.66 (m, 2H), 7.79 (m, 2H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:14]1([CH2:17][N:18]2[C:26]3[N:25]=[C:24]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][CH3:35])=[CH:30][CH:29]=4)[NH:23][C:22]=3[C:21](=[O:36])[N:20]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:19]2=[O:45])[CH2:16][CH2:15]1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH:14]1([CH2:17][N:18]2[C:26]3[N:25]=[C:24]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([N:34]([CH3:35])[C:5](=[O:7])[C:4]5[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[N:11][C:3]=5[O:2][CH3:1])=[CH:32][CH:33]=4)[NH:23][C:22]=3[C:21](=[O:36])[N:20]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[C:19]2=[O:45])[CH2:16][CH2:15]1
Reactant: COc1ccc(C(=O)O)c(OC)n1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)c(OC)n1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 2,6-dimethoxynicotinic acid (Aldrich) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 1 equivalent of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and excess triethylamine and a catalytic amount of 4-dimethylaminopyridine were added as the final reagents to the reaction mixture. The product was purified by chromatography using silica gel eluted with 9:1 ethyl acetate/hexanes followed by crystallization from acetonitrile. MS, m/z(M+)=599.2417.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:18]([NH:20][C@@H:21]([C:23]([NH2:25])=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2C=CC=CC=2)=[CH:6][CH:5]=1>CO.C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:18]([NH:20][C@@H:21]([C:23]([NH2:25])=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(N)=O

Procedure:
1 G. of the product of Example 2 was hydrogenated in methanol at TR and 1 atmosphere with 600 mg. of 10% Pd. on carbon catalyst with a few drops of glacial acetic acid for 20 hours at TR. The catalyst was removed by filtration and the methanol evaporated to dryness in vacuo. The product was lyophyllized from water to yield 500 mg. of title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)=[C:5]2[CH2:19][CH2:20][N:21]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:37]([N:21]([CH2:20][CH2:19][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:46]([N:45]([CH3:49])[CH3:44])=[O:47])[CH:3]=2)[NH:7][C:6]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of N-{4-[4-({2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}benzylamino)butyl]phenyl}methanesulfonamide (15 mg in 1.5 mL of dry methylene chloride) at 0° C. was added dimethylcarbamyl chloride (0.03 mL of a 10% v/v solution in methylene chloride) and diisopropylethylamine (0.053 mL of a 10% v/v solution in methylene chloride) and the mixture warmed to room temperature. After 3 days the reaction was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:1) to give the title compound (17 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[S:44]([CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:46])=[O:45])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)S(=O)(=O)Cc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (89 mg, 0.175 mmol) in CH2Cl2 (3 mL), alpha-toluenesulfonyl chloride (40 mg, 0.21 mmol) and triethylamine (30 μL, 0.21 mmol) are added under N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC (C18-ODB-AQ, 5 μm, 20×50 mm, YMC, eluent: CH3CN /H2O+0.1% HCOOH flow: 20 mL/min). The HPLC fractions are collected, and the resulting solution is lyophilized to afford the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.81 min.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>CC(C)=O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:17][CH2:24][CH:26]2[CH2:27][O:28]2)[CH:3]=1
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2ccccc2oc2cc(OCC3CO3)cc(O)c12
Temperature: 57.5 °C
Yield: 22.4 %

Procedure:
1,3-dihydroxy-9H-xanthen-9-one (1 g, 4.39 mmol) prepared in Step 1 of Example 2 and K2CO3 (1.52 g, 10.98 mmol) were added to a dry round-bottom flask, and anhydrous acetone (25 ml) was added thereto. Epichlorohydrin (1.73 mL, 21.95 mmol) was added dropwise to the reaction mixture, and the reaction liquid was stirred under reflux at a temperature of 55 to 60° C. for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1 (v/v)) to give the title compound (0.28 g, 22%) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5](O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:19])=O>C(O)C>[NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]([Cl:19])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(O)nc(-c2ccncc2)c(N)c1=O
Solvent: CCO
Product: Cn1c(Cl)nc(-c2ccncc2)c(N)c1=O
Temperature: 100 °C

Procedure:
5-Amino-2-hydroxy-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.46 mmol) was suspended in phosphorousoxychloride (230 mmol) at 0° C. and 2 mL ethanol was added. The reaction was heated to 100° C. overnight. The solvent was removed under vacuum. The solid was suspended in methylene chloride and collected by filtration. M+1=237.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([OH:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:21]1([C:24]([CH2:26]Br)=[O:25])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([O:20][CH2:26][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C(CBr)C1CC1
Reactant: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1OCC(=O)C1CC1
Temperature: 23 °C
Reaction time: 40 h

Procedure:
A mixture of 1.5 g of 3-chloro-2-(4-cyano-3-hydroxyphenyl)-5-trifluoromethylpyridine, 1.2 g of bromomethyl cyclopropyl ketone, 1.5 g of potassium carbonate and 50 ml of anhydrous dimethylformamide was stirred for 40 hours at 23° C. After addition of 200 ml of water, the mixture was extracted three times with 50 ml of methyl tert-butyl ether each time. The combined organic phases were washed with 50 ml of water, then dried over sodium sulfate and concentrated. The residue which remained was crystallized by triturating with n-hexane. Yield: 1.6 g of white crystals having a melting point of 115°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]1)[C:5]#[N:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(N2CCCC(O)C2)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1ccc(N2CCCC(=O)C2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 3-fluoro-4-(3-hydroxypiperidin-1-yl)benzonitrile (2.4 g, 10.90 mmol) in CH2Cl2 (50 mL) was added Dess-Martin Periodinane (6.93 g, 16.35 mmol). The reaction was stirred at rt for 1 h. The reaction was then diluted with CH2Cl2, washed with aqueous 10% Na2S2O3, saturated aqueous Na2CO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-50% EtOAc/Hex to give the product, 3-fluoro-4-(3-oxopiperidin-1-yl)benzonitrile, (730 mg, 3.35 mmol, 30.7% yield) as a white foam. Anal. Calcd. for C12H11FN2O m/z 218.2, found: 219.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([CH3:11])[C:4]=2[CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.CO/[CH:45]=[CH:46]/[C:47]([O:49][Si](C)(C)C)=[CH2:48]>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]3[CH:45]=[CH:46][C:47](=[O:49])[CH2:48][CH:7]3[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1c2ccccc2C=Nc2ccc(Br)cc21
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Product: CC1c2ccccc2C2CC(=O)C=CN2c2ccc(Br)cc21
Reaction time: 8 h
Yield: 41 %

Procedure:
To a stirred solution of 2-bromo-11-methyl-11H-dibenzo[b,e]azepine (5R8═Br; 666 mg, 2.33 mmol) ytterbium (III)triflate (146 mg, 0.23 mmol) was added. After stirring for 10 min. at room temperature Danishefsky's diene (0.89 mL, 4.66 mmol) was added. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was quenched with aqueous NaHCO3, extracted into ethyl acetate, washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica to give 8-bromo-10,14b-dihydro-10-methyl-dibenzo[c,f]pyrido[1,2-a]azepin-2(1H)-one (6, R8═Br; 338 mg, 41%). Data: (m/z)=354/356 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]1([CH3:20])[CH2:19][O:18]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]2([CH3:20])[CH2:19][O:18]2)=[CH:4][CH:3]=1
Reactant: CC1(CCl)CO1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(COc2ccc(Br)cc2)CO1

Procedure:
4-Bromophenol (80 g, 462 mmol), 2-(chloromethyl)-2-methyloxirane (400 ml) and potassium carbonate (95.86 g, 693 mmol) were mixed and allowed to react at 100° C. for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Ethyl acetate (200 ml) and water (400 ml) were added thereto, followed by extraction. The water layer was extracted with ethyl acetate (200 ml). The organic layer was washed with water (200 ml) twice. The organic layer was then concentrated under reduced pressure to remove the ethyl acetate. Thereafter, toluene was added and the resulting mixture was concentrated under reduced pressure, obtaining 120 g of crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(O)(=O)C>CCO>[CH3:1][O:2][C:3]1[C:8](/[C:9](/[NH:19][CH2:20][CH2:21][OH:22])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)nc1OC
Reactant: NCCO
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C=C(\NCCO)c1ccc(OC)nc1OC
Temperature: 90 °C
Yield: 98.2 %

Procedure:
To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-oxopropanoate (500 mg, 1.97 mmol) in EtOH (4 mL) was added 2-aminoethanol (0.60 mL, 9.9 mmol) followed by acetic acid (0.63 mL, 9.9 mmol). The reaction mixture was heated to 90° C. for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was concentrated in vacuo and the crude material was purified by chromatography on silica eluting with 20-80% EtOAc/heptane to provide the title compound (573 mg, 98%) as a clear gum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: ClCCOCCOCc1ccccc1
Product: O=C(Cc1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1

Procedure:
is prepared according to example 4c starting from 1-(4-hydroxyphenyl)-2-phenyl ethanone (prepared according examples 4a-b)(10.0 g, 47.1 mmol) and 2-(2-benzyloxyethoxy)ethyl chloride (11.0 g, 51.8 mmol). The product was triturated three times with warm heptane to remove byproducts. Yield 9.6 g, 52%. 1H NMR (CDCl3): 3.60-3.79 (m, 4H), 3.85 (dist.t, 2H), 4.16 (dist.t, 2H), 4.20 (s, 2H), 4.56 (s, 2H), 6.92 (d, 2H), 7.20-7.41 (m, 10H), 7.96 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]([CH3:38])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)(=O)C>[C:1]([O:5][C:6]([C:8]1([NH:19][S:20]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH2:10][C:9]1([CH2:17][NH:18][CH:36]([CH3:38])[CH3:35])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CC1(CN)c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)NCC1(c2ccccc2)CC1(NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
To the obtained 2-aminomethyl-1-[5-(4-chloro-phenyl)-thiophene-2-sulfonylamino]-2-phenyl-cyclopropanecarboxylic acid t-butyl ester (60 mg, 0.12 mmol) in tetrahydrofuran (1.0 mL) were added acetone (13 μL, 0.17 mmol) and sodium triacetoxyborohydride (37 mg, 0.17 mmol) at 0° C. under argon atmosphere, and the mixture was stirred at room temperature for 20 hours. To the obtained solution was added acetic acid (50 μL), and the mixture was further stirred for 21 hours. Then saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added and the aqueous layer was extracted with ethyl acetate (3.0 mL). The organic layer was washed with water (2.0 mL) and saturated aqueous sodium chloride solution (2.0 mL), and dried over magnesium sulfate. After filtration and evaporation, the obtained residue was purified by silica gel chromatography (chloroform:methanol=25:2) to give the title compound (45 mg, yield 69%) as a pale-yellow oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[Cl:28][C:29]1[CH:30]=[C:31]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[CH:14]=[C:15]2[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(Cl)c(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 3,4-dichlorobenzeneboronic acid. The title compound was obtained in 90% yield as yellow foam. MS (m/e): 516.2 (MH+, 100%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: C=O
Reactant: Oc1cccc(O)c1
Solvent: O
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
100 ml of the dried particles from Example 2 of size 10 μm were dispersed in a solution containing 150 ml water, 20 g resorcinol and 60 g formaldehyde solution (37%). The resulting mixture was kept at 70° C. for 1.5 hours under stirring. After cooling to ambient temperature the particles were separated from the reaction mixture and washed with water on a sieve of mesh size 37 μm. The particles had a diameter of 68 μm in water and shrank somewhat in air to 61 μm diameter.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32]([OH:34])=O)[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:47]([CH2:49][NH2:50])[OH:48]>CN(C)C=O>[OH:48][CH2:47][CH2:49][NH:50][C:32](=[O:34])[CH2:31][N:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)[C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])=[CH:12][CH:13]=2)=[N:18]1
Reactant: NCCO
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1)NCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (0.13 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added 1,1′-carbonyldiimidazole (0.156 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then ethanolamine (0.195 mmol) was added. The reaction mixture was stirred for another 3 h and concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded recovered starting material and the title compound as a white solid (9%). ESMS [M+H]+: 496.4
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16](COCC[Si](C)(C)C)[CH:17]=3)[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=2)=[CH:5][N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:15]1[CH:14]=[C:13]([C:11]2[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=[C:7]([C:4]3[S:3][C:2]([CH3:1])=[N:6][CH:5]=3)[N:12]=2)[CH:17]=[N:16]1
Reactant: Cc1ncc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncc(-c2cc3nccn3c(-c3cn[nH]c3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
2-methyl-5-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)thiazole (0.196 g, 0.475 mmol) was dissolved in 3 mL of DCM before TFA (2.0 mL, 26.0 mmol) was added slowly at room temperature. The reaction was allowed to stir at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure to afford the crude material. The crude material was purified via column chromatography, eluting with 5% MeOH in DCM with 1% NH4OH to afford the title compound (0.087 g, 64.9% yield). MS (apci) m/z=283.1 (M+H).