Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:11]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)sc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) was added TFA (3 mL) and the resulting mixture allowed to stir at r.t. for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 2-Azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine as a yellow oil (209 mg, 52% over two steps). 1H NMR (CDCl3, 400 MHz): δ 7.99-7.98 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.25 (2 H, m), 4.41 (4 H, brd s), 3.89-3.84 (5 H, m), 3.59 (2 H, t, J=7.25 Hz), 3.48 (2 H, s), 3.36-3.34 (5 H, m), 1.43 (3 H, t, J=7.47 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH:24][CH:21]1[CH2:23][CH2:22]1)=[O:6]
Reactant: NC1CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
2-Chloro-4,5-dinitrobenzoic acid (known from WO-A-2009/47558) (8.0 g, 32.5 mmol) was dissolved in 1,2-dichloroethane (80 ml), and thionyl chloride (20 ml) was added under nitrogen. The reaction mixture was heated under reflux for 4 h and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (80 ml) and, at 0° C., cyclopropylamine (2.4 ml, 39 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was stirred with diethyl ether (50 ml) for 30 min and then filtered off with suction. The residue was washed with water (100 ml) and dried. 7.5 g (81% of theory) of 2-chloro-N-cyclopropyl-4,5-dinitrobenzamide were thus obtained.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([N:30]1[CH2:37][CH2:36][CH:35]2[CH2:38][CH:31]1[CH2:32][CH2:33][CH:34]2[OH:39])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([N:30]1[CH2:37][CH2:36][CH:35]2[CH2:38][CH:31]1[CH2:32][CH2:33][C:34]2=[O:39])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OC1CCC2CC1CCN2Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCC2CC1CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (1.30 g) is added to a solution of 2-benzyl-2-aza-bicyclo[3.3.1]nonan-6-ol (0.60 g) in dichloromethane (15 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at ambient temperature for 1 h. Then, the solution is diluted with dichloromethane and washed with a mixture of aqueous Na2S2O3 solution and aqueous NaHCO3 solution. The solution is dried (Na2SO4) and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->2:1).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1)=[CH2:14].[Cl-].[Na+]>O.C(O)C>[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=Cc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(CC(C(=O)OCC)C(=O)OCC)cc1
Yield: 70.1 %

Procedure:
Into a flask containing 100 ml of dry ethanol were fed 2.43 g (0.106 mole) of metallic sodium, 50.77 g (0.317 mole) of diethyl malonate and 16.12 g (0.106 mole) of p-vinylbenzyl chloride in dry nitrogen gas atmosphere. The mixture was subjected to reaction at the reflux temperature for 3 hours. 100 ml of pure water was added to the reaction mixture to dissolve the sodium chloride (NaCl) generated by the reaction. Extraction was carried out with three 100 ml-portions of methylene chloride to obtain a methylene chloride solution of the product, i.e., diethyl 2-(p-vinylbenzyl)malonate.
Reaction SMILES: [CH:1]1[C:6]([NH:7][NH2:8])=[CH:5][CH:4]=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:2]=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=O)[CH:20]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:18]2>C(O)C>[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]3[N:7]([C:6]4[CH:1]=[CH:2][C:3]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][CH:5]=4)[N:8]=[C:26]([C:27]([F:28])([F:29])[F:30])[C:20]=3[CH2:19][CH2:18][C:17]=2[CH:16]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)CCc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Reaction time: 14.8 h
Yield: 63.9 %

Procedure:
4-Sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0 mmol) was added to a stirred solution of the diketone from Step 1 (1.86 g, 7.3 mmol) in ethanol (10 mL). The reaction was heated to reflux and stirred for 14.8 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, washed with water and with brine, dried over MgSO4 and reconcentrated in vacuo to give the pyrazole as a brown solid (1.90 g, 64%): mp 215-218° C. 1H NMR. (acetone-d6) 300 MHz 8.10 (d, 2H), 7.80 (d, 2H), 7.24 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 2H), 6.88 (d, 1H), 3.02 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H). 19F NMR (acetone-d6) 282 MHz −62.46 (s). High resolution mass spectrum Calc'd. for C19H17F3N3O2S: 408.0994. Found: 408.0989.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([C:19]1[CH:20]=[C:21]([N:25]2[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:30](O)=[O:31])[CH:28]=[N:27][NH:26]2)[CH:22]=[CH:23][CH:24]=1)#[CH:18]>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:30]([C:29]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[CH:18])[CH:20]=4)[NH:26][N:27]=[CH:28]3)=[O:31])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: C#Cc1cccc(N2NN=CC2(C(=O)O)c2ccccc2)c1
Solvent: CO
Product: C#Cc1cccc(N2NN=CC2(C(=O)N[C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)c2ccccc2)c1

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 1-(3-ethynylphenyl)-5-phenyl-1,2,3-triazole-5-carboylic acid by the same method as described for the title compound of Example 2 to afford a white solid, m.p. 115°-125° C. (softens at 81° C.). [α]D =-110.1° (c=0.69, MeOH).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]([CH2:24][OH:25])[CH2:21][CH2:20][CH:19]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH:24]([CH:22]1[CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:21]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC(CO)CCC1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C=O)CCC1c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (15.44 ml, 2 M in DCM, 30.9 mmol) in DCM (100 ml) was added DMSO (4.38 ml, 61.8 mmol) at −78° C. The mixture was stirred at −78° C. for 5 min. Followed by the addition of tert-butyl-5-(hydroxymethyl)-2-phenylpiperidine-1-carboxylate (3.6 g, 12.35 mmol) in DCM (10 mL). The resulting mixture was stirred at −78° C. for 15 min, then triethyl amine (13.78 ml, 99 mmol) was added. The mixture was warmed up to 0° C., quenched with NH4Cl aqueous, and diluted with ether. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was directly used in the next step.
Reaction SMILES: CN(C)C=O.C(N(CC)CC)C.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[CH3:19][N:20]([CH3:31])[CH:21]=[N:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[CH3:30]>[Cu](I)I.C(OCC)(=O)C.O>[CH3:19][N:20]([CH3:31])[CH:21]=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:25][C:24]=1[CH3:30]
Reactant: Cc1cc(I)ccc1N=CN(C)C
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C#C[Si](C)(C)C)ccc1N=CN(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 44.6 %

Procedure:
Dimethylformamide (10 ml), 10 ml of triethylamine, 0.33 g of trimethylsilyl acetylene, 0.11 g of palladium chloride-ditriphenylphosphine complex, and 0.03 g of copper iodide were added to 0.50 g of the N,N-dimethyl-N′-(4-iodo-2-methylphenyl)formamidine (Compound 2-1) produced in Reference Example 1, and the mixture was stirred at 80° C. for 12 hours. After completion of the reaction, water was added to the reaction solution, and extraction was performed 3 times with ethyl acetate. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby obtaining 0.20 g of N,N-dimethyl-N′-[2-methyl-4-(2-trimethylsilyl-1-ethynyl)phenyl]formamidine (Compound 49).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:16]1[CH:20]=[CH:19][O:18][CH:17]=1)([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[OH:10].[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])=[C:3]([C:9]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)[OH:10])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Br)cc1C(O)(c1ccoc1)c1ccoc1
Product: O=C(CCl)Nc1ccc(Br)cc1C(O)(c1ccoc1)c1ccoc1

Procedure:
Prepared from (2-amino-5-bromophenyl)[di(3-furyl)]methanol and chloroacetyl chloride generally according to procedure of described in example 1. 1H NMR (DMSO-d6): δ 10.69 (s, 1H), 8.14 (d, J=8.74 Hz, 1H), 7.69 (t, J=1.68 Hz, 2H), 7.54 (q, J=8.74 Hz, 1H), 7.51 (s, 1H), 7.32 (s, 2H), 7.02 (d, J=2.37 Hz, 1H), 6.43 (d, J=1.03 Hz, 2H), 4.26 (s, 2H); MS (ESI) m/z 408/410/412 ([M−H]−).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1>>[C:1]([C:11]1[S:10][C:9]([Cl:8])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: Clc1cccs1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(Cl)s1
Reaction time: 72 h
Yield: 52 %

Procedure:
5.9 g of activated clay (product of Nacalai Tesque, Inc.) and 25.5 g (0.25 moles) of acetic anhydride were introduced into a 100 ml 4-necked flask equipped with a stirrer, condenser, thermometer, and dropping funnel. 29.6 g (0.25 moles) of 2-chlorothiophene was added dropwise at 45° C. to 55° C. over 1 hour. After the dropwise addition, the reaction was allowed to proceed at 50° C. for 72 hours. After the reaction, the activated clay was separated by filtration to give a dark brown filtrate. The filtrate was subjected to distillation to remove unreacted 2-chlorothiophene, acetic anhydride, and by-product acetic acid, thus giving 20.9 g (0.13 moles) of 2-acetyl-5-chlorothiophene. The yield of 2-acetyl-5-chlorothiophene was 52% based on 2-chlorothiophene. The 3-isomer content was determined in the same manner as in Example 1. The 3-acetyl-5-chlorothiophene content of the resulting 2-acetyl-5-chlorothiophene product was 0.5 wt. %.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][N:14]1[C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:25]=2)=[N:17][C:16]([CH:37]=[O:38])=[N:15]1.O>CCOCC.O1CCCC1>[CH3:13][N:14]1[C:18]([NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH:25]=2)=[N:17][C:16]([CH:37]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:38])=[N:15]1
Reactant: Brc1ccccn1
Reactant: Cn1nc(C=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cn1nc(C(O)c2ccccn2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 8 h
Yield: 102.4 %

Procedure:
n-Butyllithium (1.6M in n-hexane, 8.12 ml) was added dropwise during 15 min to a stirred solution of 2-bromopyridine (1.86 g, 1.12 ml) in anhydrous ether (10 ml) at -70°, under nitrogen. The brown solution was stirred at -70° for 0.5 h before a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-carboxaldehyde (2.0 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise at -70° and the solution was stirred at -40° for 2 h before water (20 ml) was added and the mixture was allowed to stand overnight at 20°. The mixture was concentrated extracted with ethyl acetate and the extract was dried and evaporated to give an oil (2.5 g) which was chromatographed using System C as eluent to give a solid (0.48 g). This was crystallised from ethyl acetate to give the title compound (0.25 g) as a white powder m.p. 152°-154° (d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][C:25](=[O:31])[NH:24][C:23]=2[N:22]=1)[CH:8]1[CH2:13][CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][C:25](=[O:31])[NH:24][C:23]=2[N:22]=1)[CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(n1)NC(=O)CC2)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(n1)NC(=O)CC2)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
To a solution of 0.30 g of tert-butyl((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate in 12 mL of methanol, 0.10 g of potassium carbonate and 3 mL of water were added, and the mixture was stirred at room temperature for 7 hours 30 minutes. To the reaction mixture, water, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was added with sodium chloride and extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.24 g of tert-butyl((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(piperidin-4-yl)carbamate as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[N:11]=[CH:10][C:9]([N:8]3[C:6](=[O:7])[C:2]4([CH2:5][CH2:4][CH2:3]4)[NH:1][C:26]3=[O:28])=[CH:14][CH:13]=2)=[CH:17][C:18]=1[O:23][CH3:24]
Reactant: COc1cc(Oc2ccc(NC(=O)C3(N)CCC3)cn2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)NC4(CCC4)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 179.5 %

Procedure:
To a solution of 1-amino-N-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)cyclobutanecarboxamide (Intermediate 102, 60 mg) in dry dichloromethane (2 mL) TEA (0.128 mL, 0.916 mmol) was added. The reaction mixture was cooled in an ice-bath, then a solution of triphosgene (24.47 mg, 0.082 mmol) in dry dichloromethane (0.500 mL) was added dropwise. The mixture was stirred at 0° C. for 30 minutes. The reaction was maintained at 0° C. and quenched with water (10 mL). The mixture was extracted with dichloromethane (3×4 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a 25 g SNAP column and using as eluents cyclohexane/ethylacetate from 100:0 to 50:50. This afforded the title compound (52 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH2:34][C:35]([OH:37])=[O:36]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH2:34][C:35]([OH:37])=[O:36])[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CNCC(=O)O
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CC(=O)O)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-aminoyacetic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Methylamino-acetic acid following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[C:18]([CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[C:18]([CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCc1c(C)[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-ethyl-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-ethyl-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.48 ppm (s, 3H), 2.51 ppm (m, 2H), 2.34 ppm (s, 3H), 1.35 ppm (2xd, 6H), 1.09 ppm (t, 3H),
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([CH2:17][NH2:18])[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH:32]3[CH2:34][CH2:33]3)[CH:28]=2)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:32]1([C:29]2[NH:30][N:31]=[C:27]([NH:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([NH:18][CH2:17][C:4]4[CH:3]=[C:2]([F:1])[C:7]5[N:8]([CH:11]6[CH2:16][CH2:15][CH2:14][CH2:13][O:12]6)[CH:9]=[N:10][C:6]=5[CH:5]=4)[N:25]=3)[CH:28]=2)[CH2:34][CH2:33]1
Reactant: NCc1cc(F)c2c(c1)ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2ncn(C3CCCCO3)c12
Temperature: 120 °C
Yield: 62.6 %

Procedure:
A tube was charged with 270 (260 mg, 1.04 mmol), 53 (100 mg, 0.57 mmol), DIPEA (0.5 ml) in IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated under reduced pressure to afford 160 mg (34%) N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (272) as yellow solid: MS (ESI) m/z=449.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[C:23]=1[C:24](Cl)=[O:25]>CN(C=O)C.ClCCl.C(OCC)(=O)C>[F:21][C:22]1[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[C:23]=1[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:25]
Reactant: O=C(Cl)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
To a solution of methyl 4-aminobenzoate (514.6 mg, 3.40 mmol) and di-isopropylethyl amine (1.77 mL, 10.18 mmol) in DMF (10 mL) at 0° C. was added a solution of 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1 g, 3.39 mmol) in dichloromethane. The reaction was complete after 10 min. The reaction mixture was diluted with ethyl acetate and washed with water (2×200 mL), 1 N HCl (2×50 mL), and brine then dried over Na2SO4, filtered and concentrated. Silica gel chromatography using a gradient of ethyl acetate/hexane (0-100%) provided methyl 4-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate (459 mg, 33%) as an off-white solid. ESI-MS m/z calc. 409.05. found 410.3 (M+1)+; Retention time: 1.86 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.36 (s, 1H), 7.62-7.57 (m, 2H), 7.56-7.51 (m, 2H), 7.51-7.46 (m, 1H), 3.42 (s, 3H) ppm.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([O-])([O-])=O.[Tl+].N.O=O>[Pd].O1CCOCC1>[C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [Pd]
Agent: N
Agent: O=O
Solvent: C1COCCO1
Product: NC(=O)c1ccccc1
Yield: 71 %

Procedure:
In the same flask as in Example 1 were charged 2 g of benzaldehyde, 50 g of dioxane as the reaction medium and 2 g of a catalyst in which 5 percent by weight of palladium metal together with thallium nitrate with an atomic ratio of Pd to Tl being 1 to 0.1. The reaction was conducted at a reaction temperature of 40° C. by introducing ammonia gas at a rate of 1 l/hour and oxygen at a rate of 10 l/hour at the same time into the flask for 2 hours to give benzamide at a yield of 71%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[C:16]=1[CH:17]=O)[CH3:14].[BH3-]C#N.[Na+].[OH-].[Na+]>CO.[Cl-].[Cl-].[Zn+2].CCCCCC>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([NH:1][CH2:17][C:16]3[C:15]([CH2:13][CH3:14])=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:23][CH3:24])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH3:12]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: CCc1cccc(CC)c1C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: CCc1cccc(CC)c1CNc1cccn2c(C)c(C)nc12

Procedure:
8-amino-2,3-dimethyl-imidazo[1,2-a]pyridine (0.33 g, 2.0 mmol) and 2,6-diethylbenzaldehyde (0.36 g, 2.2 mmol) were dissolved in methanol (7 ml). ZnCl2 (0.30 g, 2.2 mmol) and subsequently NaBH3CN (0.14 g, 2.2 mmol) in small portions were added and the mixture was refluxed under argon for 3 hours, cooled and then poured over an aqueous 1M NaOH solution (10 ml). The resultant yellow suspension was extracted with DCM (3×25 ml) and the combined organic solutions were washed with brine, dried over Na2SO4 and then removed. The oily residue (0.4 g) was purified by flash chromatography (DCM-EtOAc 0%-20% EtOAc) to give 0.34 g. Treatment of this oily product with hexane (2 ml) afforded 0.14 g (23%) as off-white crystals.