Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:27][C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[CH2:20]3)=[O:18])[C:7](=[O:28])[CH:6]3[CH2:29][CH:30]4[CH2:31][CH2:32][O:33][C:5]34[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:27][C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[CH2:20]3)=[O:18])[C:7](=[O:28])[C:6]3[CH2:29][CH:30]([CH2:31][CH2:32][OH:33])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(NCCCCN1C(=O)C2CC3CCOC32c2cc(Cl)ccc21)N1Cc2ccncc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCCCn1c(=O)c2c(c3cc(Cl)ccc31)C(CCO)C2)N1Cc2ccncc2C1
Reaction time: 18 h

Procedure:
To a solution of N-[4-(9-chloro-5-oxo-2,3,3a,4,4a,5-hexahydro-6H-furo[2′,3′:2,3]cyclobuta[1,2-c]quinolin-6-yl)butyl]-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (30 mg, 0.064 mmol) in dimethylformamide (292 uL) and water (292 uL) was added sodium hydroxide (1.679 μl, 0.064 mmol). The solution was stirred for 18 hours and then brought to pH ˜7 by dropwise addition of 1M HCl. Column chromatography of the wet, crude mixture provided the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (s, 1H), 8.54 (d, J=5.1 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.46 (dd, J=9.1, 2.4 Hz, 1H), 7.37 (d, J=9.1 Hz, 1H), 7.25 (m, 1H), 5.06 (t, J=5.7 Hz, 1H) 4.77 (bs, 2H), 4.75 (bs, 2H), 4.33 (t, J=7.4 Hz, 2H), 3.87 (m, 2H), 3.74 (m, 2H), 3.46 (m, 2H), 3.37 (dd, J=14.0, 4.5 Hz, 1H), 2.86 (dd, J=14.0, 1.3 Hz, 1H), 2.27 (m, 1H), 1.97 (m, 1H), 1.82 (m, 2H), 1.71 (m, 2H); MS (ESI(+)) m/e 467 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)=[O:7]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)c(OC)c2)n1C
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1OC

Procedure:
The transformation of the acetic acid ester of part (A) to its acetic acid is performed according to example 11 part B to yield 5-(3′,4′-dimethoxybenzoyl)-1-methylpyrrole-2-acetic acid
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Cl:15])=[C:10]([Br:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Br)c(Cl)s2)c1Br
Yield: 25 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-5-chlorothiophene-2-sulphonyl chloride in 25% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 143-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N[C@H]1c2ccccc2C[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
5-Chloroindole-2-carboxylic acid (2.8 g, 14 mmol), tert-Butyl [(1S,2S)-2-amino-2,3-dihydro-1H-inden-1-yl]carbamate (3.47 g, 14 mmol), DIPEA (4.9 ml, 28 mmol) and HOBT (1.89 g, 14 mmol) were dissolved in DCM (100 mL), stirred for 5 mins, then EDCI (3.2 g, 16.7 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (125 mL) was added and the organic solution washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (5.7 g, 93%) as a pale brown foam.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([CH3:11])[C:17]=1[CH3:18])=[O:5]
Reactant: COc1cccc(C)c1C
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCl)c(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Chloropropionyl chloride (12.70 g, 100 mmol) is slowly added to a suspension of AlCl3 (16.0 g, 120 mmol) in CH2Cl2 (200 mL) at 0° C. under N2. Next, 2,3-dimethylanisole (13.62 g, 100 mmol) is slowly added at 0° C. The resulting yellow solution is stirred at 0° C. for 30 min, and then quenched by the addition of ice-cold 1.0 N HCl (200 mL) (the first several mL are added very slowly). The resulting mixture is stirred at room temperature for 20 min and then extracted with CH2Cl2. The extract is washed again with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to a yield white solid. 1H NMR (CDCl3, 400 MHz): 7.50 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.87 (s, 3H), 3.34 (t, J=6.8 Hz, 2H), 2.41 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [O-]Cl.[Na+].[CH2:4]([NH:10][C:11](=S)[S-:12])[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.[NH4+]>C(Cl)Cl>[CH2:4]([N:10]=[C:11]=[S:12])[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1
Reactant: S=C([S-])NCc1ccco1
Agent: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: S=C=NCc1ccco1
Temperature: 20 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A 5.25% aqueous NaOCl solution (60 ml) is added to a stirred, cooled suspension of 1.9 g of ammonium furfuryldithiocarbamate in 20 ml of CH2Cl2 at such a rate that the temperature does not exceed 6° C. The mixture is stirred one hour at 20° C. and extracted with 3×50 ml of CH2Cl2. The combined extracts are washed with H2O (2×50 ml) dried (Na2SO2) and evaporated to afford 1.13 g of (81.2% yield) of crude furfurylisothiocyanate (NMR, IR are supportive of the structure).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1
Reactant: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](OC(C)=O)CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](O)CC[C@@]21C
Yield: 91.1 %

Procedure:
A solution of 6.00 g of 3β-acetoxy-14β-ethoxymethoxy-5β-androst-15-en-17-one and 30 ml of 2N aq. sodium hydroxide in 120 ml of methanol was kept at room temperature for 24 hrs. The mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give 4.90 g of the title compound (II-ac) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[CH2:13]([C:12]1[C:11]2[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[NH:1][N:15]=1)[CH3:14]
Reactant: CCCc1ccc(C(=O)OC)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
To a solution of methyl 3-amino-4-propylbenzoate (5.07 g) in acetic acid (150 ml) was dropwise added a solution of sodium nitrite (2.07 g) in water (5 ml) for 5 min. After stirring for 20 min, the reaction mixture was concentrated, and then toluene and a saturated aqueous sodium hydrogencarbonate solution were added to the residue. The separated toluene layer was dried over sodium sulfate and concentrated. The residue was allowed to stand and partially solidified. The solid was washed with hexane and dried to give the object compound (2.44 g) as a brown solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>CN(C)C=O>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc2ccccc2[nH]1
Yield: 20.03 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 1H-benzo[d]imidazole-2-carboxylic acid (100 mg, 0.617 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (161 mg, 0.617 mmol) using N,N-dimethyl formamide as the solvent. The product was purified by flash chromatography and recrystallized from chloroform, respectively. Yield 20.03%. 1H-NMR (400 MHz; CDCl3): δ 1.33 (d, 3H), 4.32 (dd, 1H), 4.47 (dd, 1H), 4.64-4.75 (m, 1H), 6.59 (d, 1H), 7.34-7.41 (m, 2H), 7.50 (d, 1H), 7.52-7.56 (m, 1H), 7.62 (d, 1H), 7.81-7.87 (m, 2H), 8.00 (d, 1H), 8.42 (d, 1H), 10.87 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7](=[O:27])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[C:22](Cl)[N:21]=[N:20][C:19]=2[Cl:25])=[O:17])[N:13]=1.[OH-].[K+].[C:33](=O)(O)[O-:34].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7](=[O:27])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:26])[C:16]([C:18]2[CH:23]=[C:22]([O:34][CH3:33])[N:21]=[N:20][C:19]=2[Cl:25])=[O:17])[N:13]=1
Reactant: O=C([O-])O
Reactant: CN(Cc1csc(NC(=O)NCc2cccc(F)c2)n1)C(=O)c1cc(Cl)nnc1Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(Cl)nn1

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide (47 mg) was treated with potassium hydroxide (56 mg) in MeOH (5 mL) over night. The resultant mixture was diluted with water (10 mL) and the pH was adjusted to 9-10 by sodium bicarbonate. After evaporation of MeOH, the resultant precipitate-3-chloro-6-methoxypyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide was collected, briefly rinsed with water and dried. The desired product was confirmed by 1HNMR and LC-MS.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])=[O:5])[CH3:2]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=C(C)C(=O)N1c2ccccc2CC1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: To the mixture of 3.0 g of indoline-2-carboxylic acid ethyl ester, 4.3 g of powdered potassium carbonate and 30 ml of methylene chloride is added 1.64 g of methacryloyl chloride in 5 ml of methylene chloride during 1 minute. After stirring at room temperature for 3 hours the mixture is partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed with 30 ml of 1N hydrochloric acid and 25 ml of saturated sodium chloride, dried and evaporated, to yield the 1-methacryloylindoline-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(F)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(F)cc1CBr
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH2:15]
Reactant: NN
Reactant: Clc1cc2c(nn1)CCCCCC2
Solvent: c1ccncc1
Product: NNc1cc2c(nn1)CCCCCC2

Procedure:
3-Chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine (1.36 g) was treated with anhydrous pyridine (10 mL) and anhydrous hydrazine (3 mL) at 100° C. for 5.5 h. The solvent was removed under vacuum and the residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to provide 3-hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine; 1H NMR (CDCl3, 300 MHz) 6.71 (s, 1H), 3.01 (m, 2H), 2.68 (m, 2H), 1.70-1.85 (m, 4H), 1.40 (m, 4H) ppm; MS (ES) 193 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)cc1Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1Cl

Procedure:
Preparation according to Preparation 16 using 4-bromo-2-chlorophenol (6 g, 29 mmol) and acetic anhydride (13.4 g, 130 mmol) in pyridine (10.5 ml, 130 mmol). Yield 7.4 g. MS m/z (rel. intensity, 70 eV) 210 (25), 208 (bp), 206 (79), 63 (21), 62 (9), 250 (M+, 8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]([C:18]2([NH:33]C(=O)OC(C)(C)C)[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C:18]1([C:16]([NH:15][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[O:17])[CH2:19][CH2:20][N:21]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:22][CH2:23]1
Reactant: CN(C)CCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
1-(4-Chlorophenyl)-N4,N4-dimethylbutane-1,4-diamine (Intermediate 57) (330 mg, 1.46 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (526 mg, 1.46 mmol) and DIPEA (0.763 mL, 4.37 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (609 mg, 1.60 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 51.0%) as a colourless gum. tert-Butyl 4-(1-(4-chlorophenyl)-4-(dimethylamino)butylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (423 mg, 0.74 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford 4-amino-N-(1-(4-chlorophenyl)-4-(dimethylamino)butyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (245 mg, 35.8%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](N)=[C:4]([CH3:13])[CH:3]=1.[ClH:14].N([O-])=O.[Na+]>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:14])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cl
Reactant: Cc1cc(Br)c2ccccc2c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)c2ccccc2c1Cl
Temperature: 60 °C
Yield: 58 %

Procedure:
To a solution of 4-bromo-2-methyl-1-naphthlamine (10 g) in a mixture of concd. hydrochloric acid (14 ml) and water (14 ml) was added dropwise a solution sodium nitrite (2.8 g) in water (7 ml) at -5°-0° C. The diazonium solution was stirred at 0°-5° C an hour. There was added to it an ice-cooled solution of cuprous chloride (4.4 g) in concd. hydrochloric acid (25 ml). The mixture was stirred at 60° C an hour, and the precipitate was extracted with ether and dried. After evaporating the solvent, the residue was distilled to give a colorless oil(5.4 g, 58 %), bp11 127°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH:20]3[CH:15]([CH2:16][NH:17][CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2ccc3c(c2)C2CNCCC2O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.221 g, 0.53 mmol) was dissolved in CH2Cl2 (7 mL). Trifluoracetic acid (0.81 mL, 20 equiv.) was added, and the reaction mixture was stirred at rt under N2 for 2 h. The reaction mixture was cooled to −5° C. and 2N aqueous NaOH (8 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The water layer was extracted with CH2Cl2 (2×) and with 25:1 CH2Cl2:CH3OH (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Example 245 (0.16 g) was obtained in 98% yield. MS (ESI+) for C17H15Cl2NO m/z 320.1 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]([CH3:34])([CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[C:26]([Cl:32])[CH:27]=[C:28]2[Cl:31])=[N:23]1)[C:19]#[N:20]>C1COCC1>[C:19]([C:18]([NH:17][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([CH3:34])[CH2:21][N:22]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[C:26]([Cl:32])[CH:27]=[C:28]2[Cl:31])=[N:23]1)#[N:20]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-phenoxybenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=499, RT=0.79 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39].[Na]>N1C=CC=CC=1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[S:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:9]=2)[CH:3]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)ccn1
Agent: [Na]
Solvent: c1ccncc1
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
250 mg (0.65 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine (prepared as described in Example 29) were dissolved in 10 ml of dry pyridine and 87 μl of 2,5-difluorobenzensulfonylchloride were added The reaction was stirred at room temperature overnight, then poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was then triturated with diethylether, giving 300 mg of the title compound (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18][C:19]1[O:20][CH2:21][CH2:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[O:20][CH2:21][CH2:22][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)C1=C(N)OCC1
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)OCC1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 2-amino-4,5-dihydrofuran-3-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[3-(ethoxycarbonyl)-4,5-dihydro-furan-2-yl]ureido}-benzoate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10]O)[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].P(Br)(Br)[Br:14]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][Br:14])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: BrP(Br)Br
Reactant: N#Cc1cc(F)c(CO)cc1F
Solvent: ClCCl
Product: N#Cc1cc(F)c(CBr)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%).