Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](Cl)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:16]1([CH3:18])[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(Cl)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(N=[N+]=[N-])CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
A mixture of 1-benzhydryl-3-chloro-3-methyl-azetidine (2 g, 7.39 mmol) and NaN3 (0.8 g, 12.31 mmol) was dissolved in DMF (30 mL) and the mixture was stirred at 100° C. overnight. The mixture was cooled to ambient temperature and partitioned between water (150 mL) and DCM (50 mL). The organic phase was washed with brine (3×30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give 3-azido-1-benzhydryl-3-methyl-azetidine as a yellow oil (2.1 g, 100%), which was used directly in the next step. LC/MS (Table 1, Method 2) Rt=0.915 min; MS m/z: 279 [M+H]+
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][CH2:6][C:5]([C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=2)([C:8](N(OC)C)=[O:9])[CH2:4][CH2:3]1.[CH3:22][Mg+].[Br-]>C1COCC1>[F:21][C:2]1([F:1])[CH2:3][CH2:4][C:5]([C:8](=[O:9])[CH3:22])([C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[N:16][CH:15]=2)[CH2:6][CH2:7]1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A solution of 4,4-difluoro-N-methoxy-N-methyl-1-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide (700 mg, 2.34 mmol) in THF (20 mL) was added MeMgBr (11.7 mL, 35.12 mmol, 3M in Et2O) at 0° C. and stirred at room temperature for 4 h. The reaction mixture was quenched by saturated NH4Cl at 0° C. and extracted with EtOAc (2×50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude product, which was purified by flash chromatography (EtOAc: petroluem ether=1:3˜3:2) to give 1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg, yield: 59%). 1H NMR (CDCl3 400 MHz): δ8.58 (s, 2H), 2.73 (s, 3H), 2.55-2.45 (m, 2H), 2.20-1.85 (m, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:33]([F:36])([F:35])[F:34])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:19]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:15]=[N:16][C:17]=3[C:33]([F:36])([F:34])[F:35])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(-c4ccc(F)cc4)cc3)c(C(F)(F)F)nn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(-c3cc(N4CCNCC4)nnc3C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A mixture of 4-[5-(4′-fluorobiphenyl-4-yl)-6-trifluoromethyl-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (D12) (0.115 g, 0.23 mmol) and trifluoroacetic acid (2 ml) in dichloromethane (8 ml) was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and then, dichloromethane and a saturated solution of sodium carbonate were added. The organic layers were separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; 1-3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo to yield E9 (0.084 g, 91%). C21H18F4N4 requires 402; Found 403 (MH+).
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15]([N:16]2N=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[CH3:32][C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.N1(C2C(C(O)=O)=NC=CC=2)C=CC=N1>>[CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15]([N:16]2[CH:32]=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: O=C(O)c1ncccc1-n1cccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1cccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol) and 3-(1H-pyrazol-1-yl)pyridine-2-carboxylic acid (CAS number 1521232-19-8; 70 mg, 0.37 mmol) except this was purified by column chromatography (silica, 50-100% ethyl acetate/petrol then 0-10% methanol/ethyl acetate) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CNc2cccc3cccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CNc2cccc3cccnc23)cc1
Yield: 58.8 %

Procedure:
The compound obtained in Example 16-1 (1 g) was dissolved in methanol (10 ml), and 1 mol/l aqueous solution of sodium hydroxide (10 ml) was added. The reaction solution was dissolved in THF (10 ml). After the reaction for 7 hours, the reaction solution was concentrated. The obtained residue was dissolved in water and 1 mol/l hydrochloric acid was gradually added while stirring to obtain a precipitate. The precipitate was collected by filtration through glass filter G4 and washed with water to obtain the title compound (560.1 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=[O:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:52]N1CCCCC1CO.C[Zn]C>C1(C)C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:43])[CH3:52])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCCCC1CO
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: C[Zn]C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Reaction time: 1 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (0.017 g, 0.024 mmol, 1.0 equiv) and (1-methylpiperidin-2-yl)methanol (3.12 mg, 0.024 mmol, 1.0 equiv) were mixed in 1 mL toluene and concentrated to remove water. Then the mixture was re-dissolved in toluene (1.2 mL). To this solution was added 1 M dimethyl zinc (0.097 mL, 4.0 equiv) and stirred for 1 hour. It was quenched by 1 mL methanol. After concentration, the residue was used as is for the next reaction. LCMS (ESI, M+1): 720.4.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([OH:34])[CH2:31][C:32]#[CH:33])[CH:25]=1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:33]#[C:32][CH2:31][CH:30]([OH:34])[C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Reactant: C#CCC(O)c1cccnc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3cccnc3)oc21

Procedure:
Analogous to the procedures described in Example 88, 2-bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 79) is treated with 1-(pyridin-3-yl)but-3-yn-1-ol (Preparation 75) to afford the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([O:8]CC)=[O:7].C(OCC)C.O.Cl>O.C1COCC1>[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C=C(C)C#CS(=O)(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C#CS(=O)(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C)=CC(=O)O

Procedure:
NaOH (100 mg, 2.5 mmol) in water is added to a solution of ethyl 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoate (605 mg, 1.7 mmol) in 15 ml of THF. The medium is then refluxed for 6 h. Next, it is poured into an ethyl ether/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution and extracted with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The residue is then crystallized from methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:36][Zn+]>C1COCC1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([CH3:36])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Zn+]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(Br)cnc4cc3-c3ccccc3)cc2)CCC1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Temperature: 100 °C
Yield: 21.4 %

Procedure:
101 mg (0.19 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester (intermediate example Int-2-1) were dissolved in 0.95 mL THF. After addition of 0.49 mL (0.97 mmol) of methylzinc chloride (2M solution in THF) and 7.9 mg (0.01 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture was heated for 40′ in the microwave at 100° C. The reaction mixture was poured on water (30 mL) and extracted twice with ethyl acetate (50 mL each). The combined organic extracts were washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 18.5 mg of the desired compound which was 90% pure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:8][C:5]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(Cl)ccc1C
Product: CCOC(=O)c1cc(Cl)ccc1CBr

Procedure:
Reaction of ethyl 4-chloro-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-4-chloro-o-toluate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([N:6]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5].O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.Cl>[NH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([N:6]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:4](=[O:5])[C:3]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:2]=3[Cl:1])[S:8][C:9]=2[CH:15]=1
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc([N+](=O)[O-])cc3s2)cc1OC
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc3ccc(N)cc3s2)cc1OC
Temperature: 80 °C
Yield: 28.5 %

Procedure:
A mixture of 2 g (3.97 mmol) 2,4-Dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide in 25 ml DMF and 4 ml 1N HCl was treated with 2.24 g tin(II) chloride dihydrate and heated to 80° C. for 4 h. After cooling to room temperature 50 ml saturated NaHCO3 was added and the mixture was extracted with ethyl acetate. The organic phase is treated with decalit and filtered. The organic phase of the filtrate was washed with saturated NaCl, dried with MgSO4, filtered and evaporated to dryness. The residue was purified on reversed phase preparative HPLC eluting with an acetonitrile/water gradient to obtain 536 mg (29%) of the title compound as yellowish amorphous solid. MS (m/e): 474.0 (MH+, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C@H:11]([OH:26])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=3)[C:13]2=[O:25])=[CH:5][CH:4]=1)#[N:2].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C@H:11]([OH:26])[C@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[CH:20][CH:19]=3)[C:13]2=[O:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccs1
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(I)cc3)C2=O)cc1
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(-c4cccs4)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a suspension of compound 14-4 (80 mg) in THF—H2O (2 mL-0.67 mL), were added 2-thiopheneboronic acid (43 mgl), Cs2CO3 (0.44 g), and Pd(Ph3P)4 (19.4 mg). The mixture was stirred at 80° C. for 15 hours. The reaction mixture was filtered with Celite® pad and rinsed with the mixed solvent (EtOAc-MeOH=1-1). The filtrate was concentrated in vacuo and the resulting residue was washed with H2O and Et2O. The precipitate was collected by filtration to obtain compound 22-1 (35 mg) as a pale brown amorphous solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:11][C:12]1[C:13]([C:30]#[C:31][C:32]2[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:27]([S:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[N:14]=[C:13]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)[CH:33]=3)[C:12]([NH2:11])=[N:17][CH:16]=2)=[CH:23][CH:22]=1)(=[O:25])=[O:26])([CH3:29])[CH3:28]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(O)c3)n2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(OCCN4CCOCC4)c3)n2)cc1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
4-(2-Chloroethyl)morpholine hydrochloride (31.93 mg, 0.1716 mmol) was added to a stirred solution of 3-[2-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]ethynyl]phenol (45 mg, 0.1144 mmol) and K2CO3 (39.53 mg, 0.2860 mmol) in DMF (1 mL) and the reaction mixture warmed to 65° C. for 16 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 and stirred for 5 minutes. The layers were separated by filtration through a phase separation cartridge and the aqueous layer retained was washed with DCM (×2). The combined organic extracts were passed through a 5 g SCX-2 cartridge and washed with MeOH. The product was eluted by washing the cartridge with 2M NH3 in MeOH. The solvent was removed in vacuo and the material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the mono-TFA salt of the title compound as a yellow solid (29 mg, 41% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.09 (d, 6H), 3.22-3.25 (m, 2H), 3.41-3.74 (m, 7H), 4.01 (d, 2H), 4.43 (s, 2H), 6.98 (s, 2H), 7.14 (d, 1H), 7.41-7.48 (m, 3H), 7.92 (d, 2H), 8.23 (d, 2H), 8.78 (s, 1H) and 9.88 (s, 1H) ppm; (ES+) 507.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]([CH3:16])[NH:12][NH:11][N:10]=1
Reactant: Fc1ccc(Br)c(-c2nnn[nH]2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1NNN=C1c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.8 %

Procedure:
A mixture of 5-(2-bromo-5-fluoro-phenyl)-1H-tetrazole (1.0 g, 4.12 mmol), iodomethane (1.12 g, 10 mmol) and potassium carbonate (1.5 g) in dimethylformamide (5 mL) was stirred at room temperature for 16 hrs, then concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to provide 350 mg (Yield 33%) of the title compound as white crystals. 1H NMR (500 MHz, CDCl3) δ ppm: 4.00 (3H, s) 7.18–7.25 (2H, m) 7.72 (1H, dd, J=8.4, 5.0 Hz); 13C NMR (126 MHz, CDCl3) δ ppm: 34.59, 117.73, 119.58, 120.43, 127.57, 135.11, 153.43, 161.69. LC/MS m/z 257/259.
Reaction SMILES: [FH:1].[Sb](Cl)(Cl)(Cl)(Cl)Cl.Cl[C:9]1([F:21])[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][C:10]1([F:20])[F:19]>C(Cl)Cl>[F:1][C:9]1([F:21])[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][C:10]1([F:20])[F:19]
Reactant: F
Reactant: FC1(F)Oc2ccccc2OC1(F)Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: FC1(F)Oc2ccccc2OC1(F)F

Procedure:
500 ml of hydrogen fluoride, 5 ml of antimony pentachloride and 150 g of 2-chloro-2,3,3-trifluorobenzodioxane were heated in a closed vessel for 6 hours at 40° C., excess hydrogen fluoride was then drawn off, and the residue was taken up in methylene chloride, rendered alkaline and stem-distilled. The re-distillation gave 27 g of 2,2,3,3-tetrafluorobenzodioxane having a boiling point from 142° to 146° C. at 1020 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:12]2[NH:11][N:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:32]([C:29]4[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=4)(=[O:34])=[O:33])=[CH:7][CH:6]=3)[C:13]=2[C:14]([NH2:16])=[O:15])=[CH:20][CH:21]=1
Reactant: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Nc3n[nH]c(NCc4ccc(O)cc4)c3C(N)=O)cc2)cc1
Reaction time: 0.25 h
Yield: 12 %

Procedure:
3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide (150 mg) was dissolved in 25.00 mL of DMF along with TEA (211 μL, 2.50 eq.) and stirred on ice for 15 minutes. p-Toluenesulfonyl chloride (145 mg, 1.25 eq.) dissolved in 1 mL of DMF was slowly dripped into to the reaction vessel and continued to stir for 18 hrs allowing the reaction to reach room temperature. Once the reaction was complete, traces of starting material is no longer present and confirmed by HPLC, water was added to the reaction until a white precipitate formed. The white precipitate was then collected via filtration and dried under vacuum for 18 hrs (30 mg, 12% yield).
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH3:39])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:10][C:9]=1[CH3:40])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:41][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:26][C:25]=2[CH3:39])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[CH:10][C:9]=1[CH3:40])([CH3:6])[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccccc2F)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CN(Cc2ccccc2F)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Temperature: 85 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
To a solution of example 98 (400 mg, 0.68 mmol) in EtOH (20 mL) was added 1N NaOH (20 mL, 30 eq.) and the reaction was stirred at 85° C. for 2 h. When all of the starting material had disappeared, the reaction cooled, evaporated to dryness, taken up with water, neutralized with 1N HCL to pH 6 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed eluting with CH2Cl2 (100%) then CH2Cl2/MeOH (98/2) to afford the title compound as an oil (120 mg, 32%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:37]=4)[CH:27]=3)[CH2:24][C:23](=[O:39])[NH:16][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ncccn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (81 mg).