Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[N:7]#[C:8][NH2:9].[ClH:10]>O1CCOCC1>[ClH:10].[F:1][C:2]1[CH:3]=[N:4][N:5]([C:8]([NH2:9])=[NH:7])[CH:6]=1
Reactant: N#CN
Reactant: Fc1cn[nH]c1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)n1cc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-fluoro-1H-pyrazole, 28-d, (2 g, 23 mmol) and cyanamide (0.97 g, 23 mmol) in dioxane (5 mL) was added 4N HCl in dioxane (15 mL). The mixture was gently refluxed with stirring for 2 h under nitrogen. During the course of the reaction the product crystallizes. After cooling to room temperature, 10 mL of anhydrous ether was added and the mixture was allowed to stand for 30 min. The white solid was collected by filtration, washed with anhydrous ether and dried to constant weight in vacuuo providing the product, 28-e, (3 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:21])[N:9]=3)[CH:3]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-(4-Chloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.11 g, 0.3 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.09 g, 0.35 mmol) according to the general procedure VI. Obtained as a light brown solid (0.16 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:3]1=[O:15].[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[C:3]1=[O:15]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1cccc(C2CCC(=O)CC2)c1=O
Product: Cn1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1=O

Procedure:
The title compound was prepared as a white solid from the reductive amination of 1-methyl-3-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br-].[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][Zn+])#[N:15]>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([C:14]#[N:15])[CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: N#Cc1cccc(C[Zn+])c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: [Br-]
Product: COC(=O)c1cc(Cl)cnc1Cc1cccc(C#N)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 58 from methyl 2,5-dichloronicotinate and 3-cyanobenzylzinc bromide: 1H-NMR (CDCl3) δ 8.66 (1H, d, J=2.5 Hz), 8.23 (1H, d, J=2.5 Hz), 7.58–7.34 (4H, m), 4.57 (2H, s), 3.91 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31](Br)=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31]([C:37]#[N:38])=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cc(Br)ccc5cn4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cc(C#N)ccc5cn4)c3)cn2)CC1

Procedure:
Following the General Procedure for Conversion of Bromo(het)aryl to Cyano(het)aryl, 4-{4-[6-amino-5-(6-bromoisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.240 mmol) was reacted with Pd(PPh3)4 (38.9 mg, 0.0336 mmol) and zinc cyanide (28.2 mg, 0.240 mmol) in DMF (6 ml). The crude product was purified by chromatography on silica gel (8 g) eluting with DCM (100 ml), 1% (100 ml), 2% (100 ml), 3% (100 ml) and 4% (50 ml) MeOH/DCM to give the title compound as a yellow solid. MS(ES+): m/z=496.22 (100) [MH+]. HPLC: tR=2.82 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:28]=[C:27]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]3[C:15]4[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)cnc34)c2)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a slightly yellow solid (97 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.Cl.[OH:18][NH2:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:19][OH:18]
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(C(=NO)c2sccc2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture prepared from 7 g of (3-bromothien-2-yl) (3-methoxyphenyl)methanone, 3.09 g of hydroxyamine hydrochloride and 40 ml of pyridine was stirred at room temperature overnight and thereafter heated at 100°-115° C. for 4 hours. The mixture was then quenched with water, the organics were extracted into ether, and the ether solution was washed with 3N hydrochloric acid and water and dried over anhydrous magnesium sulfate. Evaporation of the ether left a residue which crystallized upon standing overnight. The crude solid was passed through a column (alumina packed in hexane) with 15% ether/hexane used as an eluent. The solid was recrystallized from ether/hexane to give a crystalline product (6.4 g, m.p. 100°-103° C.).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[CH:31][N:30]=[N:29]1>>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:39][CH:40]=2)[CH:32]=[CH:31][N:30]=[N:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(Cn2ccnn2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2ccnn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1,2,3-triazol-1-yl-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=9:1) C26H21N5O3
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:16]Br>FC(F)(F)C(O)=O.C(Cl)Cl>[Br:16][C:7]1[C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[C:9]([S:11][C:12]([F:15])([F:13])[F:14])[CH:8]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(Br)cc(SC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
24 g of finely powdered 2-nitro-4-trifluoromethylmercapto-aniline were dissolved in 50 ml of trifluoroacetic acid, and 18 g of bromine were metered in at 20° C. The mixture was then subsequently stirred at 20° C. for 3 hours and at 40° C. for a further 30 minutes and poured onto water, and the product was taken up in methylene chloride. After removal of the solvent, 31 g of 6-bromo-2-nitro-4-trifluoromethylmercapto-aniline were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Product: CCCCCCCCCCCCCCCCCC(=O)NC1=NC(=O)C2=CC=NC2=N1

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and octadecanoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[C:11]([O-:14])(=[O:13])[CH3:12].[K+].CN(C=O)C>O>[C:11]([O:14][CH2:9][C:3]1[C:4]([Br:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:13])[CH3:12]
Reactant: BrCc1c(Br)cccc1Br
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 1,3-dibromo-2-(bromomethyl)benzene (3.28 g, 10.0 mmol), potassium acetate (3.93 g, 40.0 mmol) and DMF (100 mL). The solution was stirred at room temperature for 14 h. After that time, the reaction mixture was diluted with water (900 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford an 88% yield (2.70 g) of 2,6-dibromobenzyl acetate 104g as an off-white solid: mp 62-65° C.; 1H NMR (300 MHz, CDCl3) d 7.57 (d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=7.9 Hz), 5.42 (s, 2H), 2.11 (s, 3H); MS (ESI+)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1cc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a suspension of 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (15 g, 29.6 mmol) in Tetrahydrofuran (THF) (100 mL) was added TEA (6.18 mL, 44.3 mmol) and isobutyl chloroformate (5.82 mL, 44.3 mmol). The resulting mixture was stirred at r.t. for 1 h. The mixture was then cooled down to −40° C. and a solution of DIBAL-H (49.3 mL, 73.9 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 1.5 h, when LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), warmed up to r.t. and concentrated. The mixture was diluted with sat. NH4Cl and extracted with dichloromethane (2×30 mL). The combined organic solution was then dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-ethyl-8-fluoro-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (10 g, 20.26 mmol, 68.6% yield) as a yellow solid, which was used in the next oxidation step without further purification.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH3:2][CH:1]([CH3:3])[C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH:13][C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:24])=[O:23])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Solvent: O
Product: CC(C)[C@H]1CC[C@H](C(=O)N[C@H](Cc2ccccc2)C(=O)O)CC1

Procedure:
EP1334963A discloses a method for producing nateglinide crystals from a reaction mixture containing nateglinide. The nateglinide is obtained by reacting trans-4-isopropylcyclohexane carboxylic acid chloride with D-phenylalanine in a mixed solvent of a ketone and water in the presence of an alkali, followed by neutralisation with an acid. Specific adjustment of the temperature of the mixture and the concentration of ketone solvent results in precipitation of nateglinide crystals. The ketone solvent(s) in the reaction is usually essential to proceed the reaction. However, a large quantity of acetone in the reaction causes high proportion of by-product.
Reaction SMILES: C([C:5]1[C:6]([O:12][CH3:13])=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1)(C)(C)C.Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>>[CH3:13][O:12][C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][C:7]=1[S:11][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: BrCCCOC1CCCCO1
Reactant: COc1c(S)cccc1C(C)(C)C
Product: COc1ccccc1SCCCOC1CCCCO1

Procedure:
In an analogous manner to that described in Example 44 e), by alkylating tert-butyl 2-methoxy-thiophenol with (RS)-2-(3-bromo-propoxy)-tetrahydro-pyran there was obtained (RS)-2-[3-(2-methoxy-phenylsulphanyl)-propoxy]-tetrahydro-pyran.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:17]1([CH3:29])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.Cl>[CH3:29][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:26])=[O:27]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3ccccc23)C(F)(F)F)c(C)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of 42 mg (0.18 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 45 mg, 0.21 mmol) of mesitylenesulfonyl chloride in 0.5 mL of pyridine was warmed to 45° C. The reaction was monitored by thin layer chromatography (ethyl acetate-hexanes (3:7)) indicating a new less polar product compared to the amine. After 6 hours, the mixture was cooled and diluted with 7 mL of 1 N aqueous HCl and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of 1 N aqueous HCl, 5 mL of brine, and three 5 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 62 mg (82.1%) of crude solid. The crude material was adsorbed onto silica gel and chromatographed on silica gel using dichloromethane-hexanes (gradient: 50%-100%). The material from the column was crystallized from ether-hexanes to afford 52 mg (67%) of the title compounds as a white solid, m.p. 189° C.-191° C.; MS: m/z 409.15 (M−).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-:20])=[CH:7]2
Reactant: Brc1cccc2cnccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2c(Br)cccc2c1
Temperature: 25 °C

Procedure:
To a solution of 5-bromoisoquinoline (10.65 g, 51.19 mmol) in CH2Cl2 (250 mL), m-CPBA (9.717 g, 56.31 mmol) was added and the mixture refluxed for 20 h and allowed to cool to rt. The mixture was washed with sat Na2SSO3 (75 mL), then 3×1N NaOH, then brine. The organic layer was dried w/Na2SO4, filtered and evaporated. The residue was crystallized from CH2Cl2: Et2O to yield the title compound as a white fluffy solid (4.58 g). MS (ESI pos. ion) m/z: 224 (MH+). Calc'd exact mass for C9H5BrNO: 224.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:12][C:4]1[C:2](=[O:3])[O:1][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=c1ccc2ccccc2o1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Nc1cc2ccccc2oc1=O

Procedure:
A 2-neck-flask provided with a drying tube and a dropping means in a water bath of a temperature of from 20° to 25° C. is charged with 1 mmol coumarin, and 60 ml of dioxane are added while stirring (with a magnetic stirrer) to dissolve the coumarin. Then 1,1 mmol pyridine are added while stirring, whereby a precipitate of a pyridine-aminocoumarin-complex is formed. Then 1,1 mmol phenylacetyl chloride, dissolved in 2 ml dioxane, are added dropwise within 2 minutes. The reaction mixture is stirred for 3 hours and then poured on an equal amount of ice, the mixture is acidified with 32% HCl until no more precipitate is formed. After the dissolution of the ice further HCl is added until no more precipitate is formed, then it is filtered using a sucking filter and washed with ice-cooled water until the filtrate is neutral. The obtained amide is twice recrystallized from ethanol (about 150 ml for PMC and about 30 ml for PFC) and dried sharply. The obtained coumarinyl derivatives have to be stored in a refrigerator under anhydrous and light-schielded conditions. The yields were 67 to 77% for PMC and 52 to 57% for PFC.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[CH:29]1[O:31][CH2:30]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][CH:21]=2)[CH2:30][CH:29]([OH:31])[C:28]([F:33])([F:32])[F:27])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C1CO1
Reactant: CCN(CC)c1ccc(CNc2cccc(Oc3ccccc3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCN(CC)c1ccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)cc1
Temperature: 40 °C
Yield: 17.4 %

Procedure:
The 3-[(3-phenoxyphenyl)[4-(N,N-diethylamino)phenyl]methylamine (0.69 g, 2.0 mmol) product from EX-631A and 1,1,1-trifluoro-2,3-epoxypropane (0.45 g, 4 mmol) were dissolved in 1 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.12 g, 0.1 mmol) was added, and the stirred solution was warmed to 40° C. for 4 h, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 ethyl acetate: hexane:ammonium hydroxide followed by reverse phase preparative HPLC eluting with 10% to 90% acetonitrile in water to give 160 mg (17%) of the desired 3-[(3-phenoxyphenyl)-[[4-(N,N-diethylamino)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, >95% pure by HPLC analysis. 1H NMR (CD30D) δ 7.39 (d, 2H), 7.31 (d, 2H), 7.22 (m, 3H), 7.13 (d, 1H), 6.98 (t, 1H), 6.75 (dd, 2H), 6.47 (dd, 1H), 6.20 (d, 1H), 4.03 (m, 1H), 3.90 (s, 2H), 3.58 (m, 4H), 3.36 (dd, 1H), 3.12 (dd, 1H), 1.05 (t, 6H). 19F NMR (CD30D) δ −80.51 (d, 3F). HRMS calcd. 459.2259 M+H]+, found: 459.2250.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH:18]=O)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[CH:9]=2)=[CH:25][CH:24]=1
Reactant: COCCN
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3C=O)cc1)cn2C1CCOC1
Product: COCCNCc1ccccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(N)c23)cc1

Procedure:
In a similar manner to Example 10, 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d)pyrimidin-5-yl)phenoxy]benzaldehyde (0.15 g) and 2-methoxyethylamine (56 mg) were reacted together to give 5-{4-[2-(2-methoxyethyl)aminomethylphenoxy]phenyl}-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine m.p. 66-68° C. (glassy foam).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][S:9]([CH2:11][C:12]([OH:14])=O)=[O:10])=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:56]=[CH:57][CH:58]=2)[O:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][NH2:55])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O.ClCCl>[N:40]1([CH2:46][C:47]2[CH:48]=[C:49]([CH:56]=[CH:57][CH:58]=2)[O:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][NH:55][C:12](=[O:14])[CH2:11][S:9]([CH2:8][CH2:7][NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:10])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC/C=C\COc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=O)NCCS(=O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)NCCS(=O)CC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
There was dissolved 1.64 g (0.0074 mol) of 2-[2-(ethoxycarbonylamino)ethylsulfinyl]acetic acid in 80 ml of 50% dimethylformamide-dichloromethane and added 1.13 g (0.0074 mol) of HOBt and 1.52 g (0.0074 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 1.91 g (0.0074 mol) of 4-[3-(piperidinomethyl)-phenoxy]-cis-2-butenylamine and the mixture was stirred for 18 hours at room temperature. The obtained precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1). Then the obtained crystals were recrystallized from ethyl acetate-n-hexane (1:1) to give 1.3 g of the titled compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
12.8 (18); Leu. 17.1 (16); Phe. 8.4 (8);