Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([C:18]#[N:19])(C)C.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[N:1]1([C:7]2[C:8]([C:18]#[N:19])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(N2CCCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncccc1N1CCCCC1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A mixture of 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl 1′-oxide (1.30 g, 7.30 mmol), trimethylsilyl cyanide (1.45 g, 14.6 mmol) and triethyl amine (1.47 g, 14.6 mmol) in dry CH3CN (25 mL) was heated at reflux for 16 h, yielding a red solution. The reaction mixture was then cooled to room temperature, and saturated aqueous NaHCO3 (20 mL) was added. After concentrated under reduced pressure the mixture was extracted with CH2Cl2 (4×30 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2) to afford 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonitrile as a pale yellow solid (1.26 g, 92%). 1H NMR (CDCl3) δ 1.58-1.66 (m, 2H), 1.75-1.83 (m, 4H), 3.21 (t, 4H, J=5.7 Hz), 7.34-7.38 (m, 2H), 8.19-8.22 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: ClCc1nc2cccnc2s1
Reactant: Clc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (60 mg, 0.3 mmol), 1-(2-chlorophenyl)piperazine (70 mg, 0.31 mmol), and DIEA (110 μL, 0.66 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 2.77 (m, 4H) 3.12 (m, 4H) 4.06 (s, 2H) 7.03 (m, 1H) 7.19 (m, 1H) 7.29 (m, 1H) 7.39 (dd, J=7.96, 1.40 Hz, 1H) 7.54 (dd, J=8.11, 4.68 Hz, 1H) 8.31 (dd, J=8.11, 1.56 Hz, 1H) 8.58 (dd, J=4.68, 1.56 Hz, 1H) (ESI) m/z 345 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([O:24][CH3:23])=[O:34])[CH:27]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: CO
Product: COC(=O)c1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-formyl-benzoic acid methyl ester and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3-methoxycarbonyl-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained.
Reaction SMILES: [ClH:1].N[CH2:3]C(C)C(OC)=O.[NH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14]>>[ClH:1].[NH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([O:15][CH3:3])=[O:14]
Reactant: COC(=O)C(C)CN
Reactant: CC(C)(N)CC(=O)O
Agent: Cl
Product: COC(=O)CC(C)(C)N

Procedure:
Compound AP-1 was prepared in analogy to Compound W in Example 20 by using 3-amino-3-methyl-butyric acid instead of DL-3-aminoisobutyric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][CH:28]([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:26]([CH2:27][CH:28]([OH:29])[C:30]4[N:31]=[CH:32][CH:33]=[CH:34][N:35]=4)[CH3:25])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ncccn1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ncccn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 46.3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.26 mmol), 2-(methylamino)-1-pyrimidin-2-ylethanol (Preparation 23)(59 mg, 0.39 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (10 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 2 mL of water, left overnight) gave the title compound (60 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](C(O)=O)=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]>N1C2C(=CC=CC=2)C=CC=1.O.[Cu]=O>[N+:1]([C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2o1
Agent: O=[Cu]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cccc2ccoc12
Temperature: 170 °C
Yield: 91.8 %

Procedure:
A mixture of 7-nitrobenzofuran-2-carboxylic acid (3.54 g, 17.1 mmol) and copper(II) oxide (0.16 g, 2 mmol) in quinoline (30 mL) was heated at 170° C. for 1 hour. Cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed by brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography (petroleum ether/dichloromethane 2/3) to afford the product 7-nitrobenzofuran (2.56 g, yield 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27-8.28 (d, 1H, J=2.0 Hz), 8.12-8.17 (m, 2H), 7.46-7.50 (t, 1H, J=8.0 Hz), 7.215-7.220 (d, 1H, J=2.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CCOC(C)=O>[NH2:1][C:4]1[C:5]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1ncccc1N
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of ethyl N-(3-nitropyridin-2-yl)glycinate (26 g) and 10% palladium on carbon (50% wet, 7.3 g) in AcOEt (250 mL) was hydrogenated under balloon pressure at room temperature for 8 h. The catalyst was removed by filtration. To the filtrate were added triethylamine (5.0 ml) and 10% palladium on carbon (50% wet, 7.3 g). The mixture was hydrogenated under balloon pressure at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-50% AcOEt in hexane) to give the title compound (18 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:7]>C(C(CC)=O)C>[CH2:10]([CH:4]([NH:7][C:6]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1)[CH2:5][CH3:6])[CH3:9]
Reactant: COCc1cc(N)ccc1C
Solvent: CCC(=O)CC
Product: CCC(CC)Nc1ccc(C)c(COC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 119 %

Procedure:
A mixture of 3-(methoxymethyl)-p-toluidine (9.3 g), 5 angstrom molecular sieves (19 g) and diethyl ketone (40 ml) is stirred at room temperature for 15 hours. The mixture is then filtered. Additional diethyl ketone (10-15 ml) and molecular sieves (10 g) are added to the filtrate. After 40 minutes at 40° to 50° C., the reaction mixture is filtered and then concentrated under vacuum. The crude product (9.0 g) is dissolved in methanol (50 ml) and cooled to 10° C. Sodium borohydrate (3.7 g) and methanol (25 ml) are simultaneously added in small portions. Thirty minutes after these additions, the mixture is acidified with 10% hydrochloric acid while in an ice bath. The mixture is extracted with ether and the ether extract is discarded. The aqueous extract is made alkaline and then extracted with ether. The ether extract is dried over magnesium sulfate and concentrated to yield 8.1 g of an orange oil which is more than 97% homogeneous as estimated by gas-liquid chromatography. Fractional distillation yields a product having a boiling point of 120° to 125° C. at 0.4 to 0.5 mm pressure.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:44][C:45]([N:47]1[CH2:52][CH2:51][N:50]([C:53](=[O:88])[C@@H:54]([NH:58][C:59]([C:61]2[CH:65]=[C:64]([O:66][CH2:67][C:68]([N:70]3[CH2:74][CH2:73][CH2:72][C@H:71]3[C:75](=[O:81])[NH:76][CH:77]3[CH2:80][CH2:79][CH2:78]3)=[O:69])[N:63]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[N:62]=2)=[O:60])[CH2:55][CH2:56][NH2:57])[CH2:49][CH2:48]1)=[O:46])[CH3:43]>CN(C=O)C.ClCCl>[CH2:42]([O:44][C:45]([N:47]1[CH2:52][CH2:51][N:50]([C:53](=[O:88])[C@@H:54]([NH:58][C:59]([C:61]2[CH:65]=[C:64]([O:66][CH2:67][C:68]([N:70]3[CH2:74][CH2:73][CH2:72][C@H:71]3[C:75](=[O:81])[NH:76][CH:77]3[CH2:80][CH2:79][CH2:78]3)=[O:69])[N:63]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[N:62]=2)=[O:60])[CH2:55][CH2:56][NH:57][C:5]([CH:3]2[CH2:4][C:2]2([F:8])[F:1])=[O:6])[CH2:49][CH2:48]1)=[O:46])[CH3:43]
Reactant: O=C(O)C1CC1(F)F
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCN)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCNC(=O)C2CC2(F)F)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 19 mg 2,2-Difluorocyclopropane carboxylic acid in 3 ml DMF were added 0.03 ml DIPEA, 58 mg HATU and 100 mg 4-[(S)-4-Amino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester. After stirring for 12 h it was diluted with dichlormethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 55 mg MS (ES+): m/e=756.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][C@H:6]([NH:24][C:25](=[O:27])[CH3:26])[C@H:7]([OH:23])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1.[OH-].[NH4+]>CO.ClCCl>[F:31][C:29]1[CH:28]=[C:4]([CH:3]=[C:2]([F:1])[CH:30]=1)[CH2:5][C@H:6]([NH:24][C:25](=[O:27])[CH3:26])[C@H:7]([OH:23])[CH2:8][NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1
Reactant: CCc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCN2C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCN2C
Yield: 32 %

Procedure:
Silica gel chromatography of approximately 0.1 g of N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-hydroxypropyl}acetamide using methanol/dichloromethane (8/92) with 0.1% ammonium hydroxide gave 0.032 g of N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-hydroxypropyl)acetamide [Rf(MeOH/CH2Cl2/NH4OH)=0.40; MS (ESI+) for C24H31F2N3O2 m/z 432.2 (M+H)+]. Re-chromatography of mixed fractions gave 0.011 g of a 9:1 mixture of the 4R isomer [Rf (MeOH/CH2Cl2/NH4OH)=0.35; MS (ESI+) for C24H31F2N3O2 m/z 432.2 (M+H)+] and the 4S isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][C:14]=3[Cl:23])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([NH2:20])=[CH:15][C:14]=3[Cl:23])=[CH:10][CH:9]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: N
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Temperature: 0 °C
Yield: 70 %

Procedure:
In 50 ml of ethyl acetate was dissolved 3.25 g of 4-[4-(4-chlorobenzoyl)benzyl]-3,5-dichloronitrobenzene, and 8.00 g of SnCl3.2H2O was added. The reaction mixture was refluxed for 1 hour, and then poured into ice-water. The mixture was alkalified with conc. ammonia solution, and the organic layer was collected by decantation. The aqueous layer was extracted twice with 50 ml of ethyl acetate, and the organic layers were combined, washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the above-identified compound as pale brown amorphous powder (yield: 70%).
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:14][CH2:15][CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([O:27][CH3:28])=[CH:19][C:18]1=[O:29]>O.C(N(CC)CC)C>[CH3:28][O:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]([CH2:16][CH:15]=[O:14])[C:18](=[O:29])[CH:19]=1
Reactant: COc1cc(=O)n(CCO)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(=O)n(CC=O)c2ccccc12
Reaction time: 0.17 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.11 mL of oxalyl chloride, 0.22 mL of dimethylsulfoxide was added dropwise under nitrogen atmosphere at −60° C., and stirred for 10 min. 20 mL of a dichloromethane solution containing 0.23 g of 1-(2-hydroxyethyl)-4-methoxyquinolin-2(1H)-one was added dropwise at the same temperature, and stirred for 10 min. After 0.58 mL of triethylamine was added at the same temperature, it was stirred at room temperature for 1.5 hours, and water was added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (4-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:22]=[C:23]([CH:34]=O)[NH:24][C:25]=1[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:23]4[NH:24][C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[C:21]([CH3:20])[CH:22]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C=O)[nH]c1C(=O)N1CCOCC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrol[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 4-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (66.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 105 mg (87%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.16 (br s, 1H, NH), 11.74 (br s, 1H, NH), 8.78 (br s, 1H), 8.27 (s, 1H), 7.74 (dd, J=2.2 & 6.5 Hz, 1H), 7.71 (s, 1H), 7.52 (m, 1H), 7.38 (t, J=9.1 Hz, 1H), 6.74 (s, 1H), 3.65 (m, 4H, 2×CH2z), 3.54 (m, 4H, 2×CH2), 2.15 (s, 3H, CH3). MS 483 [M++1].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:36]#[N:37])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=O)[CH3:32])[O:26][C:25]4=[O:34])=[CH:20][C:19]=3[F:35])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:36]#[N:37])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[S:47])[CH3:32])[O:26][C:25]4=[O:34])=[CH:20][C:19]=3[F:35])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(NC2(C#N)CCN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)c1ccc(NC2(C#N)CCN(c3ccc(N4C[C@H](CNC(C)=S)OC4=O)cc3F)CC2)cc1
Yield: 61 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)-N-{3-[4-(4-(4-methoxycarbonylphenylamino)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 61% yield.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[C:29]([I:31])[CH:28]=[C:27]([F:32])[CH:26]=4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[F:32][C:27]1[CH:26]=[C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[N:18][CH:19]=2)=[O:33])[CH:30]=[C:29]([I:31])[CH:28]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cc(F)cc(I)c4)cn3)CC2)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1
Product: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cc(F)cc(I)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-Fluoro-5-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared by the hydrolysis of 4-{4-[5-(3-fluoro-5-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester with LiOH monohydrate in manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid, above. The product was obtained after suspension in small volume of EtOAc, filtration and a wash with CH3CN. HRMS m/z calcd for C23H20N4O3FI [M+H]+: 547.0637. Found: 547.0634.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>CO>[N:10]1([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C1CNC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(Cl)cc(N2CCC2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
In a 25 mL sealable tube were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol), azetidine (0.21 mL, 3.05 mmol), and triethylamine (1.06 mL, 7.62 mmol) in CH3OH (10 mL). The vial was sealed and the reaction mixture was stirred overnight at 50° C. The reaction was concentrated and the resulting solid was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (314 mg, 53%) as a yellow solid. LC-MS (ES) m/z=185 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:29]([C:24]2[N:25]=[C:26]([CH3:28])[O:27][C:23]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:30])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=419.26.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([NH:14][C:15]([C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[N:19]([C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]3[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C@H:18]2[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[Cl:46])=[O:16])[CH3:13])[N+:7]=1[O-:47])(=O)C.O.NN.C(OCC)(=O)C>CO>[Cl:46][C:40]1[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=1[C@H:18]1[C@H:17]([C:15]([NH:14][CH:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][OH:4])[N+:7]=2[O-:47])[CH3:13])=[O:16])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[C@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]1[NH:34][S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CC(=O)OCc1cccc(C(C)NC(=O)[C@@H]2c3ccccc3C(=O)N([C@H]3CCCC[C@@H]3NS(C)(=O)=O)[C@H]2c2ccc(Cl)cc2Cl)[n+]1[O-]
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(NC(=O)[C@@H]1c2ccccc2C(=O)N([C@H]2CCCC[C@@H]2NS(C)(=O)=O)[C@H]1c1ccc(Cl)cc1Cl)c1cccc(CO)[n+]1[O-]
Yield: 68.6 %

Procedure:
To a solution of 777 mg of {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]-1-oxidopyridin-2-yl}methyl acetate in 17 ml of methanol was added 0.21 ml of hydrazine monohydrate, followed by stirring for one week. Ethyl acetate was added thereto, followed by stirring for a while and concentrating, and the residue was purified by silica gel column chromatography (eluent:chloroform-methanol). Ethyl acetate and diisopropyl ether were used to make a powder, thereby obtaining 501 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)-1-oxidopyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[I-:13].[Cs+].II.I.N(OCCC(C)C)=O.C(=O)(O)[O-].[Na+]>C(#N)C.[Cu](I)I>[I:13][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)CCON=O
Agent: I
Solvent: CC#N
Product: O=C1NC(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 46.9 %

Procedure:
Commercially available 4-aminophthalimide (500 mg, 3.08 mmol) was dissolved in acetonitrile (15 mL). To the mixture were added cesium iodide (961 mg, 3.70 mmol), iodine (947 mg, 3.70 mmol), and copper iodide (712 mg, 3.70 mmol) at room temperature, and then an 11% aqueous hydrogen iodide solution (15 mL) and isoamyl nitrite (1.24 mL, 9.24 mmol) at 0° C. The mixture was stirred at room temperature for 6.5 hours, and then for 1.5 hours after adding isoamyl nitrite (4.96 mL, 37.0 mmol). Then, saturated sodium bicarbonate was added to the mixture, and after filtration through sellite, the organic layer was separated. The resulting organic layer was washed with a saturated aqueous sodium thiosulfate solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was triturated with chloroform, and the resulting solid was filtered off and dried to give 4-iodophthalimide (394 mg, 47%).