Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](S(C)=O)[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>O1CCCC1>[CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:31][CH2:32][CH2:33][CH2:34][OH:35])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc2c(-c3ccnc(S(C)=O)n3)c(-c3ccc(F)cc3)nn12
Reactant: NCCCO
Solvent: C1CCOC1
Product: CCCCNc1cccc2c(-c3ccnc(NCCCO)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (50 mg, 0.12 mmol) and 3-amino-1-propanol (0.45 mL, 5.9 mmol) in 2 mL tetrahydrofuran was heated to reflux for 4 hours, then the mixture was cooled to room temperature and concentrated. Flash column chromatography eluting with a gradient of 0% to 100% ethyl acetate in hexanes afforded 3-({4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinyl}amino)-1-propanol (46.3 mg, 90%) as a yellow foam. 1H NMR (CDCl3): δ 7.97 (d, 1H), 7.67–7.61 (m, 3H), 7.35 (t, 1H), 7.16 (t, 2H), 6.34 (d, 1H), 6.04 (m, 2H), 3.67–3.60 (m, 4H), 3.39 (q, 2H), 1.79–1.45 (m, 6H), 1.00 (t, 3H); 19F NMR (CDCl3): δ −113.10; MS m/z 435 (M+1).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:31])[CH2:4][CH2:5][N:6]1[C:13](=[O:14])[C@H:12]([OH:15])[C@H:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[S:10][C:9]2=[CH:24][CH:25]=[CH:26][C:27]3=[CH:28][CH:29]=[CH:30][C:7]1=[C:8]23.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:15][C@@H:12]1[C@H:11]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[S:10][C:9]2=[CH:24][CH:25]=[CH:26][C:27]3=[CH:28][CH:29]=[CH:30][C:7](=[C:8]23)[N:6]([CH2:5][CH2:4][N:3]([CH3:2])[CH3:31])[C:13]1=[O:14])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Reaction time: 17 h
Yield: 90 %

Procedure:
A mixture of 3.4 g of (+)-cis-2,3-dihydro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one hydrochloride and 60 mL of acetic anhydride was stirred under nitrogen at 100° for 17 hours. The excess of reagent was removed under reduced pressure, then to the residue ice-water was added and made basic with 10% sodium hydroxide. The resulting suspension was extracted with ether (3×75 mL) and the combined ether solutions were washed with brine and dried (magnesium sulfate). Removal of the solvent under reduced pressure gave 3.1 g (90%) of (+)-cis-3-(acetyloxy)-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one as an amorphous compound, [α]D25 +187.94° (C 0.47, methanol).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].Cl[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][C:13](=[O:15])[CH3:14])([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CC(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccccc1C(C)C
Reaction time: 6 h
Yield: 112.2 %

Procedure:
A mixture consisting of 24.0 g of o-isopropylphenol, 17.0 g of chloroacetone, 30 g of potassium carbonate, 1.0 g of potassium iodide and 150 ml of acetone was heated at reflux with stirring for 6 hr. The reaction mixture was concentrated under reduced pressure; the condensate was extracted with ethyl acetate; the ethyl acetate layer was washed consecutively with 5% aqueous solution of sodium hydroxide, water and saturated saline, and thereafter dried with anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure and yielded 38 g of 2-isopropylphenoxyacetone.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([Br:21])=[C:13]([C:22]2[CH:27]=[CH:26][C:25](Cl)=[CH:24][CH:23]=2)[N:12]=1)=[O:10].BrC1N=C(C(F)(F)F)C(C(O)=O)=NC=1C1C=CC=C([Cl:42])C=1>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:19])([F:18])[F:20])=[N:15][C:14]([Br:21])=[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:42])[CH:23]=2)[N:12]=1)=[O:10]
Reactant: O=C(O)c1nc(-c2cccc(Cl)c2)c(Br)nc1C(F)(F)F
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(Br)nc1C(F)(F)F

Procedure:
This compound was prepared in analogy to example 1b (5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) by substituting 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid with 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid. MS (M−H) at 477.9 and 476.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)=[O:29])[CH3:26]>CN1C(=O)CCC1.O>[CH2:25]([O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:20]2[N:19]=[C:18]([C:15]3[N:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:10]4=[N:17][CH:16]=3)[CH:23]=[CH:22][N:21]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]
Reactant: Clc1nccc(-c2cnc3c(OCc4ccccc4)cccn23)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 8-benzyloxy-3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.19 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (0.29 g) in NMP (1 mL) was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT, diluted with water, and the resulting solid separated, washed with water, and dried. The solid was titurated with hot EtOAc and filtered to provide 4-[4-(8-benzyloxy-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (compound 8, 0.25 g), which was used without further purification.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:39][C@H:40]1[CH2:42][O:41]1>C(O)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:30][CH3:31])=[C:7]([CH:5]4[CH2:6][N:3]([CH2:39][C@@H:40]([OH:41])[CH3:42])[CH2:4]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH:27]([F:29])[F:28])[C:20]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Yield: 5.6 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (51 mg, 0.10 mmol, racemic intermediate from Example 73, Step 6) and triethylamine (57 pt, 0.41 mmol) in ethanol (1.7 mL) was added (S)-(−)-methyloxirane (18 μL, 0.26 mmol). The resulting mixture was heated at 90° C. for 3 h, and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.7 mg, 5.3%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClF3N6O2 (M+H)+: m/z=485.2; Found: 485.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH:18]=[CH2:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:19][CH:18]=[CH2:17])=[O:6]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(F)c1
Temperature: 100 °C
Yield: 55 %

Procedure:
Into a round bottom flask, there are introduced 5.35 g (35 mmoles) of 3-fluoro-4-hydroxybenzoic acid and 50 ml of allyl alcohol. 1.5 ml of concentrated sulfuric acid are added and the mixture is heated to 100° C. for 12 hours. The reaction medium is evaporated to dryness and 200 ml of water are added. The reaction medium is neutralized with sodium bicarbonate and extracted with dichloromethane. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column by eluting with an 80:20 mixture of dichloromethane and hexane. 3.7 g (55% yield) of the expected ester having a melting point of 42°-43° C. are recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=[O:31])[CH3:30]>>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])=[CH:36][C:37]([F:49])=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][C@@H:21]([CH3:23])[N:20]([CH:24]4[CH2:25][O:26][CH2:27]4)[CH2:19][C@@H:18]3[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 69.1 %

Procedure:
Following the procedures as described for compound 108f, reaction of 104e (268 mg, 0.60 mmol) and 104o (289 mg, 0.60 mmol) afforded 104p as a yellow solid (300 mg, 85%). LCMS: [M+H]+ 724
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CN1CCNCC1
Product: CN1CCN(CCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 1-Methyl-piperazine were converted to yield 3-(4-Bromo-phenyl)-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]isothiazole as colorless oil, MS: 446 (MH+,1Br).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])[CH:5]=[CH:4][N:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccnc(Cl)n2)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccnc(Cl)n2)c1

Procedure:
A solution of 2-chloro-4-(2-fluoro-5-nitrophenyl)pyrimidine (800 mg, 3.2 mmol) in ethanol (300 ml) was reduced under 40 psi hydrogen with platinum(IV) oxide (100 mg) for 30 minutes then filtered to give a solution of 3-(2-chloropyrimidin-4-yl)-4-fluorophenylamine: MS (ES+) m/z 224 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O([CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][C:3]=1[F:9]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(OCC(F)(F)C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and 2,2,3,3,3,-pentafluoropropyl triflate with potassium carbonate in acetone at ambient temperature for 18 hours. Kugelrohr distillation provided a colorless oil, b.p. 105-110° C./12 mbar.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[C:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]1([CH2:31][CH2:32][CH2:33][C:34]([NH:18][C:15]2[CH:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=4[C:2]([F:1])([F:23])[F:24])[CH2:11][CH2:10]3)=[CH:13][CH:14]=2)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(CCCc1ccccc1)Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridin-3-amine (225 mg, 0.7 mmol), 4-phenylbutyric acid (131 mg, 0.8 mmol), HATU (380 mg, 1.5 mmol) and DIPEA (465 μL, 2.7 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. After dilution with water, the mixture was extracted with EtOAc. The EtOAc extract was washed with diluted brine, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 40-70% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave a light brown gum which solidified on standing. Swishing with hexanes-Et2O (1:1) gave the title compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:22])=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH:42]=1)#[N:26]
Reactant: COc1ccc(CN(CCN(C)CCCN)c2ccccn2)cc1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: COc1ccc(CN(CCN(C)CCCNC(=NCCCOc2cccc(CN3CCCCC3)c2)NC#N)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.52 g (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil which crystallises from absolute ether at -20° C.; MS (+FAB method): m/z (rel. int. [%])=627 ([M+H]+, 6), 241 (11), 121 (100); IR (KBr): 2165 cm-1 (C≡N); m.p.: 62°-65° C. (ether).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([NH:27][C:28]([O:30]C)=O)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].C[O-].[Na+].Cl>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:17]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=[CH:25][C:26]=3[NH:27][C:28]2=[O:30])=[CH:11][CH:10]=1)#[N:2]
Reactant: COC(=O)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 89.5 %

Procedure:
To a solution of methyl 2-[(2′-cyanobiphenyl-4-yl)methylamino]-3-methoxycarbonylaminobenzoate (10.5 g) in methanol (100 ml) was added NaOMe (10 g), and the mixture was heated under reflux for 20 hours. The reaction mixture was neutralized with 1N-HCl and concentrated to dryness. The residue was extracted with chloroform-water. The organic layer was washed with water, dried and evaporated to dryness. The resulting crystals were recrystallized from chloroform-methanol to afford colorless needles (8.67 g, 89%), m.p. 250–253° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][NH:26]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:26]1[C:27]2[C:23](=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=4)[N:3]=3)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 120 °C
Yield: 11 %

Procedure:
To a mixture of 2-chloro-N-(1H-indazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.27 mmol) and 4-aminobenzamide (0.055 g, 0.4 mmol) in nBuOH (1 ml) was added TMSCl (0.017 ml, 0.14 mmol). After heating at 120° C. for 24 h, the mixture was purified by preparative HPLC to give 4-(4-(1H-indazol-4-ylamino)-7-tosyl-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (0.016 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl[C:9]1[CH:14]=[C:13]([Cl:15])C=C(Cl)C=1>>[Cl:15][C:13]1[CH:14]=[CH:9][C:1]([O:4][C:5]2[CH:3]=[CH:2][C:1]([OH:4])=[C:7]([CH2:7][CH:6]=[CH2:5])[CH:6]=2)=[CH:2][CH:3]=1
Reactant: C=CCOCC=C
Reactant: Clc1cc(Cl)cc(Cl)c1
Product: C=CCc1cc(Oc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C

Procedure:
The crude allyl ether from step 3 (20.0 g) was dissolved in 2,4,6-trichlorobenzene (60 mL) and the solution was heated at reflux for 4 h. After being cooled to room temperature, the solution was directly loaded onto a column of silica gel and eluted sequentially with hexane and a 8:2 mixture of hexane and ethyl acetate to give 4-(4-chlorophenoxy)-2-(2-propenyl)phenol.
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][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][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][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][CH3:27])[CH2:5][CH2:6]2)=[CH:32][CH:31]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(OC)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-methoxybenzyl chloride to form 1-(4-methoxybenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 233°-245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.ClCCl.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:7]=[CH:8][N:9]=2)[N:4]=1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(C#C[Si](C)(C)C)c2n1

Procedure:
1,1,1-Trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (10 g, 32 mmol) was partially dissolved in triethylamine (80 mL) and dichloromethane was added in small portions until solid was completely dissolved. The resulting solution was degassed and purged with nitrogen, then treated with (trimethylsilyl)acetylene (5 mL, 36 mmole), bis-(triphenylphosphine)palladium (II) chloride (456 mg, 0.65 mmole), and copper (I) iodide (125 mg, 0.65 mmol) at room temperature overnight. Reaction mixture was concentrated to near dryness, then redissolved in ethyl acetate and washed with water and brine. Insoluble material was filtered off and aqueous layer was dried over sodium sulfate, filtered and concentrated. The resulting brown thick oil was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:24])=O)=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:24])=[CH:19][CH:20]=2)[O:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: O=C(NC1CCOc2cc(C(=O)O)ccc21)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CCOc2cc(C(=O)Nc3ccncc3)ccc21)OCc1ccccc1
Yield: 118.7 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 7 using 4-(benzyloxycarbonylamino)chromane-7-carboxylic acid (1.6 g), thionyl chloride (1.2 ml) and 4-aminopyridine (480 mg), the objective 4-(benzyloxycarbonylamino)-N-(4-pyridyl)chromane-7-carboxamide (2.34 g) was obtained as colorless crystals.