Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]4)[CH:12]=3)=[CH:10][C:3]=12.ClC1C=CN=C2N(S(C3C=CC(C)=CC=3)(=O)=O)C(C3C4=N[C:50](OC)=[C:51]([O:53]C)C=C4N(CCCN4CCC(O)CC4)C=3)=CC=12.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:15]4=[N:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=[C:14]4[N:13]([CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([CH2:50][CH2:51][OH:53])[CH2:29][CH2:28]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3[nH]1)cn2CCCN1CCC(O)CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCC(O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3[nH]1)cn2CCCN1CCC(CCO)CC1

Procedure:
1-{3-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dimethoxypyrrolo[3,2-b]pyridin-1-yl]propyl}piperidin-4-ol can be prepared as in example 5, stage 5(d), but starting with 0.368 g of 1-(3-{3-[4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxypyrrolo[3,2-b]pyridin-1-yl}propyl)-piperidin-4-ol and 0.857 g of potassium hydroxide in 25 cm3 of methanol. 0.188 g of 2-(1-{3-[3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dimethoxypyrrolo[3,2-b]pyridin-1-yl]propyl}piperidin-4-yl)ethanol is thus obtained with the following characteristics:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]Cl>C(#N)C>[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: ClC/C=C\CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OC/C=C\CCl
Yield: 106.8 %

Procedure:
A stirred mixture of 4-hydroxy-3-methoxyacetophenone (16.6 g, 10 mmole), K2CO3 (14 g, 100 mmol) and cis-1,4-dichloro-2-butene (Aldrich, 15 g, 120 mmol) in acetonitrile (250 ml) was heated at reflux for 2.5 hours. The mixture was filtered and concentrated to an oil. Purification was by flash chromatography. The fractions containing the purest product were combined and concentrated to give white crystals, 7.7 g, 30%. This was recrystallized from ether to give analytical pure (Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (2.72 g), m.p.=64°-66° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH:17](O)(C)C>>[CH3:17][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:13][CH2:12]1
Reactant: CC(C)O
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C1CNCCN1
Product: CN1CCN(c2nc3ccccc3[nH]2)CC1
Reaction time: 6.5 h

Procedure:
2-chlorobenzimidazole (5.0 g) and piperazine (8.0 g) were dissolved in 10 ml isopropyl alcohol and reflexed 6.5 hours. The solution was concentrated in vacuo. The residue treated with sodium carbonate and then extracted with chloroform to yield 5.55 g product. mp. 222°-224° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:23]=2)=[CH:20][C:19]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[CH:36][N:35]=2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:53])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>CCOC(C)=O>[Br:53][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[C:22]([C:21]3[C:16]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:17][CH:18]=[C:19]([C:34]4[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:41])=[O:42])=[CH:36][N:35]=4)[CH:20]=3)[O:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CBr)cc4)no3)c2)nc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
tert-Butyl N-tert-butoxycarbonyl-N-[5-(5-isopropylsulfonyl-2-pyridyl)-3-[3-(p-tolyl)isoxazol-5-yl]-2-pyridyl]carbamate (245 mg, 0.3860 mmol) was suspended in EtOAc (2.5 mL) followed by the addition of NBS (89.31 mg, 0.5018 mmol) and AIBN (6.338 mg, 0.03860 mmol). The mixture was heated to 85° C. and placed under a bright lamp for 2 hours. The reaction mixture was cooled to ambient temperature and washed with saturated aqueous NaHCO3/brine (1:1, ×2), dried (MgSO4), filtered and concentrated in vacuo to give the impure sub-title compound as a pale brown foam. This was used in the next step without any further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:30][S-:31].[Na+].O>CN(C)C=O>[CH3:30][S:31][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH2:28][CH3:29])[N:20]=[CH:19][N:18]=2)=[CH:12][CH:13]=1
Reactant: C[S-]
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCSC)cc1
Yield: 75.8 %

Procedure:
A solution of ethyl 4-(2-(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.70 g, 1.66 mmol) in N,N-dimethylformamide (10 ml) was stirred under ice-cooling. Sodium thiomethoxide (0.13 g, 1.85 mmol) was added to the solution. The mixture was stirred under ice-cooling for 2 hours, and then water (40 ml) was added. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-(2-methylthioethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.47 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH:23]([OH:25])[CH3:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:15][CH:14]=3)=[O:9])=[CH:26][CH:27]=1
Reactant: CC(O)C#Cc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: C#C
Solvent: CO
Solvent: ClCCl
Product: CC(O)CCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 2.17 h
Yield: 28 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide from Example No. 152 (106.3 mg) and Pd/C (10%, 21.3 mg) is dissolved in 40 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 34 psi H2 and monitored by mass spectroscopy for complete reduction of the acetylene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction is taken off the Parr. In this case, the reaction is taken off the Parr twice. The reaction is complete in 130 min . The reaction mixture is filtered over celite to remove the palladium. The filtrate is condensed to obtain a solid. The crude product is adsorbed onto silica and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 30.0 mg (28%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:28][CH2:27][CH2:26]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(I)C=C>C(OCC)(=O)C.CCCCCC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH:15]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:28][CH:27]=[CH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
Combine (S)-4-benzyl-3-(3,4-dichlorophenyl)acetyl-2-oxazolidinone (13.9 g, 38.2 mmol) and tetrahydrofuran (140 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of sodium bis(trimethylsilyl)amide (42 mL, 1.0 M in tetrahydrofuran, 42 mmol). After 30 minutes, add allyl iodide (19 g, 114.5 mmol) and then replace the bath with a dry-ice/carbon tetrachloride bath. After 1 hour, partition the reaction the reaction mixture between a saturated aqueous ammonium chloride solution and diethyl ether. Separate the layer, dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give (S)-4-benzyl-3-(2-(3,4-dichlorophenyl)pent-4-enoyl)-2-oxazolidinone: Rf=0.50 (silica gel, 20% ethyl acetate/hexane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](O)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][C:28]=2[NH2:38])=[CH:22][CH:21]=1)(=O)C>>[Cl:33][C:31]1[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:28]2[N:38]=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[N:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][OH:17])=[CH:21][CH:22]=3)[C:27]=2[CH:32]=1
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(NC(=O)OC(C)(C)C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from N-(tert-butoxycarbonyl)-alanine and 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step 2).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[NH2:36][CH:37]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=1)[C:38]([N:40]([CH2:44][CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH:41]([CH3:43])[CH3:42])=[O:39]>CN(C=O)C.C(Cl)CCl>[Cl:59][C:56]1[CH:55]=[CH:54][C:53]([CH2:52][CH:37]([NH:36][C:33](=[O:35])[CH2:32][CH2:31][NH:30][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[C:38]([N:40]([CH2:44][CH:45]([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])[CH:41]([CH3:42])[CH3:43])=[O:39])=[CH:58][CH:57]=1
Reactant: COc1ccc(S(=O)(=O)NCCC(=O)O)cc1
Reactant: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)CCNS(=O)(=O)c1ccc(OC)cc1)C(C)C)OCC
Reaction time: 12 h

Procedure:
52 mg of EDC, 45 mg of HOBt and 100 μl of N-ethylmorpholine are added to a solution of 124 mg of 3-(4-methoxybenzenesulfonylamino)propionic acid in 1 ml of DMF. A solution of 100 mg of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide in 1 ml of DMF is added dropwise thereto, and the mixture is left to stir for 12 h. The reaction solution is filtered, mixed with ethyl acetate and then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying of the organic phase with Chromabond XTR is followed by concentration under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=598.16 (calculated); measured value (M-C2H6O+H)+: 552.1
Reaction SMILES: I[C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1.C[Sn](C)C.C[Sn](C)C.[C:45]([N+:49]#[C-])(C)(C)C.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[C:45]([C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:5][C@@H:4]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1)#[N:49]
Reactant: Cc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: [C-]#[N+]C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: Cc1cn([C@H]2C[C@H](C#N)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
The following preparation should to be performed under a hood and all precautions taken not to inhale any of reagent fumes. A suspension of 3'-deoxy-3'-iodo-5'-O-tritylthymidine (Verheyden, et al., J. Org. Chem. 1970, 35, 2868) (60 g, 0.1 mol), hexamethylditin (36 g, 22.7 ml, 0.11 mol), t-butylisocyanide (166 g, 225 ml, 2 mol), and AIBN (1.6 g, 10 mmol) in toluene (freshly distilled over Na/benzophenone, 2 lt) was thoroughly deoxygenated by bubbling argon through the reaction mixture for 30 min. and then heated at 80° C. for 13 h. The reaction mixture was cooled at 60° C. and AIBN (1.6 g, 10 mmol) was added and heating continued for 24 h. During this period addition of AIBN was repeated for 3 times in an identical manner. The reaction mixture was cooled to room temperature and transferred on the top of a prepacked silica gel column (1.5 kg, in hexanes) and eluted with hexanes: Et2O (100% hexanes→100% Et2O with a 10% gradient change each time using 1 lt of eluent). Most of the impurities were removed during the gradient elution as non-polar compounds. Final elution with Et2O (2 lt), pooling and evaporation of appropriate fractions gave two compounds in the order these were collected. (i) 12.93 g (25%) of 3'-C-Cyano-3'-deoxy-5'-O-tritylthymidine as white powder (crystallized from toluene/Et2O, mp 153°-157° C.); 1H NMR (CDCl3) δ 8.83 (s, 1, NH), 7.04-7.4 (m, 18.5, TrH, C6H, and 0.5 ArH from toluene), 6.10 (dd, 1, H1', J1',2' =4.1 Hz, J1',2" =7.1 Hz), 4.20 (m, 1 , H4', J3',4' =8.4 Hz, J4',5' =2.8 Hz), 3.33-3.60 (m, 3, H5', 5", 3'), 2.68 (m, 1, H2', J2', 2" =13.8 Hz), 2.52 (m, 1, H2"), 2.28 (s, 1.5, 0.5 CH3 from toluene), and 1.50 (s, 3, CH3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:22])=[C:13]([CH:21]=2)[CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:41]([O:42][CH3:43])=[CH:40][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:22])=[C:13]([CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])[CH:21]=2)=[N:7][C:2]([NH:24][C:25]2[C:41]([O:42][CH3:43])=[CH:40][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: CCN(CCO)Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1F
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: CCN(CCO)Cc1cc(Nc2nc(Nc3cc4c(cc3OC)CCN(CC(=O)N(C)C)CC4)ncc2Cl)ccc1F

Procedure:
The title compound was prepared from 2-{[5-(2,5-Dichloro-pyrimidin-4-ylamino)-2-fluoro-benzyl]-ethyl-amino}-ethanol and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide in an analogous manner to example 730 (0.047 g, 43%). Mp 71-75° C. LCMS (m/e) 600 (M); 1H-NMR (DMSO, 400 MHz) δ 8.90 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 7.59 (s, 1H), 7.58-7.48 (m, 3H), 7.10-7.02 (t, 1H, J=9.09 Hz), 6.78 (s, 1H), 4.35-4.25 (t, 1H), 3.77 (s, 3H), 3.59 (s, 2H), 3.46-3.45 (q, 2H, J=6.06 Hz), 3.35-3.20 (br, 2H), 3.05 (s, 4H), 2.82 (s, 4H), 2.73 (br, 2H), 2.65-2.52 (m, 4H), 0.98-0.94 (t, 3H, J=7.08 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([CH3:9])[CH:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:9][N:5]1[C:6](=[O:8])[CH2:7][CH:3]([CH2:2][O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1C(=O)CC(CO)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2c2ccccc2)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
To 27.8 g. of 3-hydroxymethyl-1-methyl-2-phenyl-pyrrolidin-5-one in 40 ml. of potassium hydroxide dried pyridine was added in portions of 0°-5° 29.4 g. of p-toluenesulfonyl chloride. The orange solution was then stirred at 15° C. for 4 hours and then decanted into 180 ml. of ice cold 10% hydrochloric acid. The resulting solid was collected by filtration and washed with water and air dried. Washing with ether provided 37 g. of crude product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38]>CN(C=O)C.O>[NH2:39][C:37](=[O:38])[CH2:36][N:20]1[C:21]2[C:17](=[CH:16][C:15]([NH:14][C:12]([C:8]3[CH:7]=[C:6]([N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:24][CH2:25][CH3:26])[N:11]=[CH:10][N:9]=3)=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: NC(=O)CBr
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(N)=O)c2)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), potassium iodide (1 mg) and 2-bromoacetamide (160 mg; 1.16 mmol). After stirring at RT for 72 hours the mixture was poured in water (20 ml) and stirred at RT for 1 hour. The solid was removed by filtration, washed with water and dried. The residue was purified by column chromatography (silica) eluting with EtOAc containing increasing amounts of MeOH to give the title compound as an off-white solid, together with N-[2-(2-amino-2-oxoethyl)-2H-indazol-5-yl]-6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxamide (Example 118 below).
Reaction SMILES: Cl([O-])=O.[Na+].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[F:14].S(N)(=O)(=O)[OH:16].C(O)(C)(C)C>C(OCC)(=O)C.O>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:16])=[O:11])=[CH:8][C:7]=1[F:14]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 101.7 %

Procedure:
Sodium chlorite (17 g) was added portionwise to a mixture solution composed of 4-chloro-3-fluorobenzaldehyde (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, and the mixture was stirred for 4 days while the temperature of the system was gradually raised to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)[N:3]=1.[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-:36].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:26]([OH:36])(=[O:19])[CH3:31].[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][CH:28]=3)=[N:3]2)[CH2:13]1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: CC(=O)O
Product: CN1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.08 h
Yield: 120 %

Procedure:
A solution of racemic 3-iodo-1-(1-methyl-3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.050 g, 0.00014 mol) in dimethoxyethane (2.5 mL) and water (5 mL) was treated with 4-phenoxyphenylboronic acid (0.033 g, 0.00015 mol), sodium carbonate (0.037 g, 0.00037 mol) and tetrakis(triphenylphosphine) palladium (0) (0.016 g, 0.000014 mol) at 80° C. for 18 hours. The organic solvent was removed in vacuo, and the crude material was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile-0.1M ammonium acetate over 15 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 1-(1-methyl-3-piperidyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.040 g, 0.00009 mol).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24](C)(C)[CH3:25])[CH2:17][CH2:16]2)[CH:10]=1.FC(F)(F)[C:32](O)=[O:33].C([O-])(O)=O.[Na+].C(N(CC)CC)C.ClC(OCCOC)=O>O.C(Cl)Cl>[F:1][CH:2]([F:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][CH2:24][CH2:25][O:33][CH3:32])[CH2:17][CH2:16]2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(-c3ccccc3C(F)F)ncn2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: COCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCOC(=O)NC1CCN(c2cc(-c3ccccc3C(F)F)ncn2)CC1
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 1-(6-(2-(difluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (0.05 g, 0.1 mmol), CH2Cl2 (0.5 mL), and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 minutes. The reaction was made basic with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and evaporated. The residue was dissolved in CH2Cl2 (0.4 mL) and triethylamine (16 μL, 0.12 mmol), and the reaction was cooled in a dry ice/acetone bath. 2-Methoxyethyl chloroformate (16 μL, 0.1 mmol) was added, and the reaction was stirred for 15 minutes. The reaction was diluted with H2O and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4 and evaporated. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 2-methoxyethyl 1-(6-(2-(difluoromethyl)phenyl)pyrimidin-4-yl)piperidin-4-ylcarbamate. LC/MS: m/z 407.4 (M+H)+ at 2.18 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).