Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2cccc(F)c2)ncc1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 6.9 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.5 mg (0.1 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[S:27])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccccc1C(=S)Nc1ccc(Br)cc1
Temperature: 25 °C
Yield: 178.3 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluorobenzamide (3.3 g, 0.0112 mol) and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.27 g, 0.00561 mol) was heated in toluene at reflux under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:6) as mobile phase to yield N1-(4-bromophenyl)-2-fluoro-1-benzenecarbothioamide (3.1 g, 0.010 mol) as a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](SC)=[NH:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=1)([CH3:3])[CH3:2].[CH:19]([NH:21]N)=O.C[N:24](C=O)C>>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:21]=[CH:19][NH:24][N:12]=2)[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CSC(=N)c1cc(OC(C)C)nc(C(F)(F)F)c1
Reactant: NNC=O
Product: CC(C)Oc1cc(-c2nc[nH]n2)cc(C(F)(F)F)n1

Procedure:
In a 50 ml capacity 3-neck round-bottomed flask attached with nitrogen bubbler, reflux condenser & magnetic stirrer methyl 2-isopropoxy-6-(trifluoromethyl)pyridine-4-carbimidothioate (5 g), formic hydrazide (0.431), dissolved in 50 ml DMF at RT for 20 min to form uncyclised form of 2-isopropoxy-4-(1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyridine which was confirmed by mass and on TLC as a polar spot as compared to starting material. Heated the reaction mixture at 80-90° C. for 6 h, which gave a non polar spot as compared to uncyclised form. The completion of the reaction was confirmed by TLC with 50% EtOAc-hexane as mobile phase. The reaction mixture was poured in ice water solution & extract with ethyl acetate (3×200 ml). Organic layer dried over Na2SO4 and concentrated to give crude product (5 g). The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 5% to 25% ethyl acetate in hexane. Compound started eluting with 25% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure 2-isopropoxy-4-(1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyridine (3.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH2:12])=O)=[CH:4][CH:3]=1.Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:15]3[N:16]=[C:17]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=[CH:19][C:14]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: Clc1ccc(-c2cccs2)nn1
Product: Fc1ccc(Cc2nnc3ccc(-c4cccs4)nn23)cc1

Procedure:
The title compound was prepared as described in Example 17 from 4-fluorophenylacetic acid hydrazide (1.04 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.52 mmol) as a pale beige solid. 1H NMR (CD3OD) δ 8.19 (1H, d, J=9.9 Hz), 7.93 (1H, dd, J=3.8 Hz, 0.9 Hz), 7.90 (1H, d, J=9.9 Hz), 7.75 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.50 (2H, dd, J=9.0 Hz, 5.3 Hz), 7.24 (1H, dd, J=5.3 Hz, 3.8 Hz), 7.06 (2H, t, J=8.8 Hz), 4.59 (2H, s). ESI-MS (m/z): Calcd for C16H11FN4S: 310.1; found 311.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16].Cl>O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][S:15]([CH3:14])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-hydroxybenzoic acid (3.45 g, 20 mmol) and sodium hydroxide (2.40 g, 60.0 mmol) in 30 ml of water is added, dropwise at 0°, methanesulfonyl chloride (2.57 ml, 3.80 g, 33.0 mmol). After addition is complete, the reaction mixture is stirred at RT for 30 min., after which it is poured into water, acidified with dil. HCl and extracted with ether. The combined organic extracts are washed with brine, dried and evaporated to give 2-chloro-4-methylsulfonyloxybenzoic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Cl:16][C:17]1[N:22]=[CH:21][C:20](I)=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:15])=[CH:12][CH:11]=2)=[CH:19][N:18]=1
Reactant: Clc1ncc(I)cn1
Reactant: C#Cc1ccc(C(C)C(=O)NCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)C(C)c1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1.10 g (5.46 mmol) N-ethyl-2-(4-ethynyl-phenyl)-propionamide (XVII.1) in 10 mL THF are added 1.31 g (5.46 mmol) 2-chloro-5-iodo-pyrimidine under argon, followed by 0.42 g (0.60 mmol) Pd(PPh3)2Cl2 as catalyst, 57 mg (0.30 mmol) copper(I)iodide and 2.1 mL (12 mmol) DIPEA as base. The mixture is stirred at rt for 4 h. After that time, the mixture is filtered and the solvent is evaporated from the filtrate. The residue is purified by column chromatography (silicia gel; DCM:MeOH gradient 1:0/1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[CH2:7][C:8](=[O:13])[NH:9][C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>ClCCl.O>[CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[CH2:7][C:8](=[O:13])[N:9]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC(=O)C2
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(CN2C(=O)Cc3cc(OC)c(OC)cc3CC2=O)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
3 g of 7,8-dimethoxy-1H-3-benzazepine-2,4(3H,5H)-dione (12.8 mmol), 2 g of 4-methoxy-benzyl chloride (12.8 mmol, 1 eq), 2.64 g of K2CO3 (19.1 mmol, 1.5 eq), 1.06 g of KI (6.4 mmol, 0.5 eq) and 30 mL of acetonitrile are introduced into a 100-mL three-necked flask. The reaction mixture is heated at 80° C. for 3 hours 30 minutes. 1 g of 4-methoxybenzyl chloride is introduced three times and the reaction mixture is held at 80° C. for 24 hours. After returning to ambient temperature, 30 mL of water and 30 mL of dichloromethane are introduced. After extraction and drying of the organic phase, the dark red oil obtained is purified by flash chromatography on a silica column (eluant: dichloromethane/methanol 99/1) to obtain the title product.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]=2)[NH:3]1.O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])[CH:8]=2)[NH:3]1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 80 °C
Reaction time: 12 h
Yield: 1114.7 %

Procedure:
4 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)acetic acid are dissolved in 100 ml of ethanol, and 300 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h, and the solvent is subsequently removed in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate and stirred at 60° C. for a further 12 h. The mixture is neutralised using sodium hydrogencarbonate, and the organic phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo, giving 4.1 g of ethyl 2-(2,3-dioxoindolin-5-yl)acetate;
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[S:25][CH:26]=[C:27]([CH2:28]Br)[C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:28][C:27]2[C:23]3[CH:22]=[C:21]([Cl:20])[CH:31]=[CH:30][C:24]=3[S:25][CH:26]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2csc3ccc(Cl)cc23)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), (5-chlorobenzo[b]-thiophen-3-yl)methylbromide (288 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.125 g (29.0%); MS m/z: 432.6 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.64 (s, 2H); 4.85 (s, 2H); 6.79 (d, 1H, 4J=2.1 Hz); 6.84 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.12-7.14 (m, 2H); 7.20-7.21 (m, 2H); 7.37 (d, 1H, 3J=8.9 Hz); 7.40 (dd, 1H, 4J=1.8 Hz, 3J=8.5 Hz); 7.47 (s, 1H); 7.93 (d, 1H, 4J=1.8 Hz); 7.94 (s, 1H); 8.00 (d, 1H, 3J=8.5 Hz); 12.18 (br s, 1H); HPLC (METHOD [A]): rt 19.69 min (100%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Li+].[CH3:14]C([N-]C(C)C)C.IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of methyl 2-(4-bromophenyl)acetate, 7-d, (1.0 g, 4.4 mmol) in THF (5 mL) was cooled to −78° C. under nitrogen, and slowly treated with LDA (2 M in THF, 2.2 mL, 4.4 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 min, and then a solution of iodomethane (0.6 g, 4.4 mmol) in THF (10 mL) was added dropwise and the mixture was stirred at −78° C. for another 30 min and then warmed up slowly to room temperature and stirred overnight. The reaction mixture was concentrated and then crush ice was added. Then the mixture was added saturated aqueous ammonium chloride (10 mL) and extracted by EA. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound, 7-e, (650 mg, 61%). 1H NMR (300 MHz, CDCl3) δ1.49 (d, J=7.2 Hz, 2H), 3.67-3.72 (m, 4H), 7.17 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H). LC-MS (M+H)+ 243, 245.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:16][OH:17]>CCO>[OH:17][NH:16][C:1](=[NH:2])[N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl 4-cyanopiperazine-1-carboxylate (15 g, 76 mmol) in EtOH (150 mL) was added hydroxylamine (50% aqueous solution, 6.2 mL, 92 mmol) and the reaction mixture was stirred at RT for 6 hours. The solvent was evaporated under vacuum. The residue was triturated with hexane (100 mL) and filtered to give 15 g (80%) of The title compound as a solid. TLC—CHCl3/MeOH (9/1): Rf=0.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:50][CH:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:51])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (635 mg, 2.6 mmol) was heated at 140° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, dichloromethane:methanol, 50:1) and then further purified by prep-HPLC to afford (4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (30 mg, 7.1%).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([N:7]2[CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][C:8]2=[O:23])[CH2:3]1.[ClH:24]>CO.[Pd]>[Cl-:24].[F:1][CH:2]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH2+:10][CH2:9][C:8]2=[O:23])[CH2:3]1
Reactant: Cl
Reactant: O=C(OCc1ccccc1)N1CCN([C@H]2CC[C@@H](F)C2)C(=O)C1
Agent: [Pd]
Solvent: CO
Product: O=C1C[NH2+]CCN1C1CCC(F)C1
Product: [Cl-]
Reaction time: 2 h

Procedure:
A stirred solution of NN2 (1 eq) and Pd/C (10% w/w, 0.3 eq) in MeOH (0.1 M) was hydrogenated under an H2 in presence of 6 M HCl (1 eq). After 16 h the catalyst was filtered off and volatiles were removed under reduced pressure. The resulting crude was again dissolved in MeOH (0.1 M) and new Pd/C catalyst (10% w/w, 0.3 eq) and 6 M HCl (1 eq) was added, and the reaction was hydrogenated for further 2 h. Then the catalyst was filtered off and volatiles evaporated, the resulting crude was used as such in the next step. MS (ES) C9H16FN2O requires: 187 found: 188 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([OH:25])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24]>O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:23]([OH:24])([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][OH:25])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OCCOCCOCCOCCO
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(O)(COCCOCCOCCO)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
p-Nitrobenzoyl chloride (390 g. 2.1 mole) and tetraethylene glycol (194 g, 1.0 mole) were dissolved in dry tetrahydrofuran (1 l) and the mixture evaporated under reduced pressure. The resulting thick oil was stirred under high vacuum (0.5 mm) overnight, during which time the mixture solidified. The mixture was slowly heated to 60° C. and maintained at this temperature for 5 hours. On cooling, the product was dissovled in ethyl acetate (2 l), saturated aqueous sodium bicarbonate (2 l) added and the mixture stirred at room temperature for 24 hours. The phases were separated, the organic phase washed with saturated sodium bicarbonate (3×), dried (MgSO4), filtered and the filtrate evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to give bis-(4-nitrobenzoyl)-tetraethylene glycol (406 g), m.p. 57.5°-58.5° C., which was homogeneous by TLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:28]([NH:30]C(=O)OC(C)(C)C)([CH3:29])[C:27](=[O:38])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[C:3]2[C:28]([NH2:30])([CH3:29])[C:27](=[O:38])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)NC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(N)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The intermediate from Step A (111 mg, 0.205 mmol) was dissolved in DCM (2.0 mL) and trifluoroacetic acid (0.39 mL, 5.12 mmol). The solution was stirred overnight at room temperature. The reaction was then diluted with EtOAc and washed with 1N NaOH aq. (twice) and brine. The solution was then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a MeOH/EtOAc gradient to give the indicated product. m/z=443.1 (M+H).
Reaction SMILES: [Cl:1]C([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH2:6][CH2:5]1)=O.N1CCNCC1.C(N)(=O)CC>C1(C)C(C)=CC=CC=1.II>[ClH:1].[C:10]([N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)(=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)N1CCN(C(=O)Cl)CC1
Agent: C1CNCCN1
Agent: CCC(N)=O
Agent: II
Solvent: Cc1ccccc1C
Product: CCC(=O)N1CCNCC1
Product: Cl

Procedure:
The 1-chlorocarbonyl-4-propionylpiperazine used as starting material can be prepared as follows. Anhydrous piperazine (120 g.) and propionamide (m.p. 80° C., 102 g.) in anhydrous xylene (100 cm3) are heated under reflux for 48 hours in the presence of iodine (0.9 g.) to give 1-propionylpiperazine hydrochloride (153.0 g.), m.p. 165° C. 1-Propionylpiperazine is liberated from its hydrochloride by the action of an excess of ammonia in diethyl ether. The ammonium chloride formed is separated by filtration and the 1-propionylpiperazine is isolated by evaporation of the ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[O:14]1CCCC1.Cl[N:20]1C(=O)C[CH2:22][C:21]1=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:22][C:21]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3([C:12]#[N:13])[CH2:10][CH2:11]3)=[CH:5][CH:4]=2)=[CH:2][O:14][N:20]=1
Reactant: C#Cc1ccc(C2(C#N)CC2)cc1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nocc1-c1ccc(C2(C#N)CC2)cc1

Procedure:
To a mixture of 1-(4-ethynylphenyl)cyclopropanecarbonitrile (200 mg, 0.001 mol) acetaldoxime (71 mg, 0.0012 mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added N-chlorosuccinimide (160 mg, 0.0012 mol) in portions with stirring. After the addition was complete, triethylamine (170 μL, 0.0012 mol) was added. The mixture was stirred at rt for 2 days. The reaction mixture was diluted with ethyl acetate and washed with water and brine successively, dried over MgSO4 and filtered. The filtrate was concentrated to afford the desired product in quantitative yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1.[C-:12]#[N:13].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[O:9]1[C:5]2[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:11]=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: BrCc1ccc2ccoc2c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc2ccoc2c1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
A mixture of 6-bromomethylbenzofuran (4.38 g, 0.021 mol), sodium cyanide (2.0 g, 0.041 mol), tetrabutylammonium bromide (0.42 g, 0.0013 mol), water (15 cm3) and dichloromethane (15 cm3) was stirred vigorously for 18 hr. The mixture was separated and the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was extracted with petroleum ether (b.p. 60°-80° C.), and the solvent was removed to give benzofuran-6-acetonitrile (3.09 g, 0.0197 mol), 93.7%) as an oil, t.l.c./silica/toluene, RF 0.21.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 141.2 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.65 g, 5 mmol) and 5% palladium carbon (0.8 g) in ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl[4-(4-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.11 g, 94.2%) as crystals.