Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:5])=[O:4].C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[CH3:15][N:2]([CH3:1])[S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([Br:23])[CH:13]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCc1ccc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.2 %

Procedure:
A solution of 737 mg (3.23 mmol) of 2-(4-amino-phenyl)-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (20 mL) was cooled to 0° C. and treated with 574 mg (3.23 mmol) of NBS. The ice bath was removed and the mixture stirred at RT for 25 min. The mixture was diluted with CH2Cl2 (40 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The aqueous layer was extracted with CH2Cl2 (1×30 mL) the combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 955 mg (96%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 7.35 (d, 1H, J=2.0 Hz), 7.04 (dd, 1H, J=8.0, 2.0 Hz), 4.44 (br s, 2H), 3.21-3.14 (m, 2H), 2.96-2.89 (m, 2H), 2.84 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C10H15N2OSBr, 307.0/309.0 (M+H). found 307.0/309.0.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1>C(O)C.O.[Pt](=O)=O>[CH3:1][CH:2]1[NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: CC1CCCC(C(=O)O)N1
Reaction time: 72 h
Yield: 95.4 %

Procedure:
6-Methyl-pyridine-2-carboxylic acid (4.11 g, 30 mmol) was mixed with platinum(IV) oxide (35 mg, 0.154 mmol) in ethanol (50 mL) and water (25 mL) and stirred under hydrogen for 3 days. The reaction mixture was filtered through the celite and concentrated to dry. The residue was triturated with diethyl ether to give 4.1 g (98.3%) of the title compound as a white solid. 1H NMR (CDCl3), δ(ppm): 3.39 (dd,1H), 3.11 (m, 1H), 2.28 (d, 1H), 1.88 (m, 2H), 1.35–1.67 (m, 3H), 1.32 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[Cl:16][C:17]1[C:18]([OH:28])=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[C:21]([Cl:23])[CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][S:24]([C:19]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[C:18]=2[OH:28])(=[O:25])=[O:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of 2-amino-indan-2-carboxylic acid ethyl ester (3.14 g, 15.3 mmol) and 3,5-dichloro-2-hydroxy-benzenesulfonyl chloride (1 g, 3.82 mmol) in anhydrous DCM (dichloromethane, 20 mL) is added DIPEA (631 μL, 3.82 mmol). The resulting solution is stirred at RT for 1 hour. The reaction solution is diluted in DCM (50 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (30) as white solid (450 mg, 27%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18]>CCOCC>[C:17](=[O:18])([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:19][CH:20]([Cl:22])[CH3:21]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCCCCCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a stirring solution of dry n-octanol (6.42 g, 49.3 mmol) and pyridine (3.90 g, 49.3 mmol) in anhydrous ether (75 mL) was added at 0° C. alpha-chloroethyl chloroformate (prepared according to U.K. Pat. No. 1,426,717; 7.00 g, 49.3 mmol). The mixture was stirred vigorously for three hours at 25° C. then filtered. The filtrate was concentrated in vacuo and distilled at 102°-107° C. (2 mm) affording 8.1 g title product as a clear oil (34.2 mmol, 69.4%): 1H NMR (CDCl3) delta 0.44-2.03 (m, 15H), 1.60 (d, J=6 Hz, 3H), 3.94 (t, J=7 Hz, 2H), 6.18 (q, J=6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:63])([F:62])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[C:51]([C:58]([O:60][CH3:61])=[O:59])[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:55][CH2:54][N:53]2[C:49]([C:48]([F:63])([F:47])[F:62])=[N:50][C:51]([C:58]([O:60][CH3:61])=[O:59])=[C:52]2[CH2:57]1)=[O:5]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 22.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), crude methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (300 mg, 1.50 mmo) and N,N-diisopropylethylamine (0.4 mL, 2 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate 3 (120 mg, yield 23.0%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:22])=[N:14][C:15]4[C:20]([N:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=[C:4]2[N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:22])=[N:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:21]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: NC1CCOCC1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(Cl)n2n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-2-yl)-2-methylquinoxaline (991 mg, 3.00 mmol), 4-aminotetrahydropyran (364 mg, 3.60 mmol), and triethylamine (1.25 mL, 9.00 mmol) in N,N-dimethylformamide (30 mL) was stirred for 2 h at room temperature. After being cooled to 0° C., the reaction mixture was diluted with water. The resulting precipitate was collected and purified by silica gel column chromatography (silica gel 200 g, chloroform to chloroform:ethyl acetate=1:1) to give 5-chloro-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine. MS (APCI): m/z 395/397 (M+H).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][Cl:7])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24]2[C:29]=1[CH:28]=[CH:27][C:26]([Cl:30])=[CH:25]2)=[O:20])[CH3:17]>CS(C)=O>[ClH:7].[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH2:3][CH2:2][N:4]([CH2:8][CH3:9])[CH2:5][CH3:6])[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24]2[C:29]=1[CH:28]=[CH:27][C:26]([Cl:30])=[CH:25]2)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.2 g. of 2-diethylaminoethyl chloride hydrochloride in 35 ml. of dimethylsulfoxide is treated with 8.3 g. of finely ground dry potassium carbonate and stirred at room temperature for 15 minutes. Then, there are added thereto 3.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester; the mixture is stirred intensively for 18 hours under an atmosphere of nitrogen at room temperature and subsequently poured onto 80 ml. of ice-water. After the addition of 5 g. of sodium chloride, the separated oil is immediately extracted with ether, and the extract concentrated to about 30 ml. and treated with 30 ml. of 0.5-N hydrochloric acid. The mixture is thoroughly shaken and cooled in an ice-bath. The crystallized hydrochloride is isolated and purified in an analogous manner to that given in Example 1, and there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 248°-250° C. (decomposition).
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:17](OCC)=[O:18])(=O)[CH3:14]>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:16]2[C:13]([CH3:14])=[N:2][N:1]([C:3]3[NH:7][C:6]4[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=4[N:4]=3)[C:17]=2[OH:18])=[CH:28][CH:27]=1
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccc(Cl)cc4)c3O)nc2c1

Procedure:
Using 2-hydrazino-5-methyl-1H-benzimidazole (4) obtained in Example 1, step 3 and ethyl 2-acetyl-3-(4-chlorophenyl)propanoate (31), and by a method similar to that in Example 1, step 4, 4-[(4-chlorophenyl)methyl]-3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-5-ol (32) was obtained.
Reaction SMILES: [Cl: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)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(C)=O>[Cl: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)[S:7][C:6]=2[C:5]([O:17][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCBr
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCOc1ccc(Cl)c2c(=O)c3ccccc3sc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
1-Chloro-4-dodecyloxythioxanthone was prepared as follows. A solution of 1-chloro-4-hydroxythioxanthone (14.0 g, 0.05 mol), K2CO3 (8.09, 0.06 mol) in acetone (250 mL) was stirred and refluxed for 10 min. Bromododecane (20.0 g, 0.08 mol) was added and the resulting mixture was stirred for 24 h under reflux. The reaction was then cooled to room temperature and quenched with water (500 mL). The obtained solid was filtered, washed with water, purified by recrystalized from isopropanol to give the 1-chloro-4-dodecyloxythioxanthone (14.3 g, 62%) with mp 79–80° C. The identity of this compound was shown by 1H NMR to have the following structure:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl.C(N(CC)C(C)C)(C)C.[Cl:65][C:66]1[N:71]=[C:70](Cl)[CH:69]=[CH:68][N:67]=1>CC(O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:45])=[N:25][C:26]=2[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:70]2[CH:69]=[CH:68][N:67]=[C:66]([Cl:65])[N:71]=2)[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](NC(=O)OC(C)(C)C)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: Clc1ccnc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CC[C@H](Nc6ccnc(Cl)n6)CC5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Temperature: 60 °C

Procedure:
(2R,3R,4R,5R)-2-(2-Chloro-6-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydrofuran-3,4-diyl diacetate (Intermediate 1) (5.4 mmol) was treated with 1:1 trifluoroacetic acid/dichloromethane (20 ml) at room temperature for ca. 1 h. This was concentrated in vacuo and the residue was partitioned between dichloromethane (50 ml) and aqueous sodium bicarbonate (50 ml). The organics were washed with aqueous sodium bicarbonate (50 ml), dried over sodium sulfate and concentrated in vacuo to give a white solid. This was dissolved in propan-2-ol (100 ml). To this was added N,N-diisopropylethylamine (4 m. eq.) and 2,4-dichloropyrimidine (1 m. eq.). The reaction mixture was heated at 60° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organics were washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by SPE (50 g, silica) eluting with x% ethyl acetate in dichloromethane where x=25, 50, 75. Fractions containing desired product were combined and concentrated in vacuo to yield the title compound as a colourless gum, 1.49 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10](Cl)=[O:11].[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Product: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.9 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride and 1.4 ml of tert.-butanol were reacted to obtain 1.43 g of tert.-butyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+67°±4° (c=0.25% in benzene).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[OH:11][C:12]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14]
Reactant: C1CCNC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2O1
Solvent: C1CCOC1
Product: O=C(CCc1ccc([N+](=O)[O-])cc1O)N1CCCC1
Reaction time: 1 h

Procedure:
The crude 7-nitro-chroman-2-one (1.1 g, approx. 4.2 mmol) was dissolved in tetrahydrofuran (15 ml). Pyrrolidine (0.35 ml) was added and the reaction mixture stirred for 1 hour. The solution was adsorbed onto silica and eluted using methanol in dichloromethane. 3-(2-hydroxy-4-nitrophenyl)-1-pyrrolidin-1-yl-propan-1-one was obtained as a brown solid (900 mg, 3.40 mmol);
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:38]=[N:37][C:26]4[NH:27][C:28]5[CH:33]=[N:32][C:31]([C:34]([OH:36])=O)=[CH:30][C:29]=5[C:25]=4[CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.N.O1CCOCC1.S(=O)(=O)(O)O>CN(C=O)C.CS(C)=O>[CH3:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:38]=[N:37][C:26]4[NH:27][C:28]5[CH:33]=[N:32][C:31]([C:34]([NH2:3])=[O:36])=[CH:30][C:29]=5[C:25]=4[CH:24]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(=O)O)cc5c4c3)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(N)=O)cc5c4c3)cc2)CC1
Reaction time: 0.17 h

Procedure:
DIPEA (14 μL, 77 μmol) was added to a solution of 3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid (20.0 mg, 51.6 μmol), PyBOP (28.2 mg, 54.2 μmol) and HOBt (8.4 mg, 62 μmol) in DMF (1 mL). After 10 min at ambient temperature, a solution of 0.5M ammonia in 1,4-dioxane (500 μL, 0.258 mmol) was added to the reaction mixture. After 30 min the reaction mixture was acidified with 10% aqueous sulfuric acid and made homogeneous with the addition of DMSO. The crude solution was purified by preparative HPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.48 (s, 1H), 9.11-8.89 (m, 4H), 7.77 (d, J=8.9 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 3.97 (d, J=13.5 Hz, 2H), 3.55 (q, J=12.2 Hz, 2H), 3.20 (q, J=11.4 Hz, 2H), 3.03 (t, J=12.0 Hz, 2H), 2.89 (s, 3H). LCMS (Method D): RT=6.35 min, M+H+=387.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH:11]([C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][CH:15]=1)([CH3:13])[CH3:12].[OH-].[Na+]>ClC(Cl)C.O>[CH:11]([C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15]=1[CH:4]=[O:5])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: Cc1cc(C(C)C)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(C)C)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a solution of anhydrous DMF (2.1 ml, 27 mmol) in anhydrous dichloroethane (50 ml) at 0° C. under nitrogen, POCl3 (2.1 ml, 23 mmol) was added dropwise. The solution was allowed to warm at room temperature for 1 h. Then, the suspension was cooled at 0° C. and a solution of 3-isopropyl-5-methylpyrrole (2 g, 16 mmol) in dichloroethane (20 ml) was added dropwise over 20 min. After stirring at room temperature for 24 h, water followed by NaOH were added to pH: 8. The organic layer was extracted, dried and the solvent removed to dryness. The residue was purified by flash chromatography. Yield 67%, m.p. 90–93° C.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:12]([C:13](O)=O)=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.[Cl-].[Cl-].[Cl-].[Al+3]>[CH2:1]([CH:3]([NH:6][C:7]1[CH:8]=[C:9]([CH3:26])[N:10]=[C:11]([NH:16][C:17]2[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])[C:12]=1[CH3:13])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C

Procedure:
The title compound was prepared by reduction of 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic acid with 1M of lithium aluminium hydride in diethyl ether and aluminium trichloride at reflux. 1H NMR(CDCl3)6.9(s,2H), 6.0(s,1H), 5.4(brs,1H), 3.6(d,1H), 3.3(m,1H), 2.32(s,3H), 2.2(s,3H), 2.15(s,6H), 1.4-1.7(m,4H), 1.0(t,6H) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparations 78 and 79 using 4-fluoro-2-methoxy-1-nitrobenzene and 1-methylpiperazine. The residue was purified by silica gel column chromatography eluting with 0-20% MeOH in EtOAc.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C=O.[C:48](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][N:40]([CH3:48])[CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCN(C)CC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (D80, 100 mg, 0.16 mmol) in 5 mL of acetonitrile was added a 37% aqueous formaldehyde solution (24 μL, 0.32 mmol). The solution was stirred at room temperature for 30 min, and then sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in dichloromethane and extracted with water and brine. The product was purified by flash chromatography (silica, dichloromethane to dichloromethane: MeOH 95:5). Obtained 58 mg of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:16]([NH2:18])[CH3:17])[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13].[NH2:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][N:21]=1>>[NH2:19][C:20]1[N:25]=[C:24]([C:26]([NH:18][CH:16]([C:6]2[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[C:4]([O:3][CH3:2])[CH:5]=2)[CH3:17])=[O:27])[CH:23]=[CH:22][N:21]=1
Reactant: COc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: Nc1nccc(C(=O)O)n1
Agent: Cl
Product: COc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Yield: 51 %

Procedure:
The title compound is prepared in 51% yield (95 mg, a white solid) from 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (144 mg, 0.50 mmol, Amine-22, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (70 mg, 0.50 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[C:45]([O:48][CH2:49][CH3:50])(=[O:47])[CH3:46]>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([O:13][CH:49]([O:48][C:45](=[O:47])[CH3:46])[CH3:50])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(C)=O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5-carboxylic acid (910 mg, 2.1 mmol, prepared as described in part C of Example 9), the title B compound (930 mg, 7.6 mmol), sodium iodide (795 mg, 5.03 mmol), cesium carbonate (2.6 g, 7.98 mmol) and dimethylformamide (4.0 mL) were combined and were stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate and filtered. The organic phase was washed with pH=4 buffer twice, pH 7 buffer once, saturated sodium chloride once, dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil. Purification by chromatography on Merck silica gel (250 g) eluting with (8:2) hexane/ethyl acetate gave the title B compound (1.06 g).