Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:36]=[CH:35][C:11]([C:12]([NH:14][CH2:15][C:16]([N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)(C(OC)=O)[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].Cl>O1CCCC1.CO.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][CH:16]([N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)[C:17]([OH:19])=[O:18])=[O:13])=[CH:35][CH:36]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.4 %

Procedure:
0.5 ml (0.5 mmol) of an aqueous solution of sodium hydroxide having a concentration of 1N are added to a solution of 100 mg (0.2 mmol) of dimethyl 2-[(4-but-2-ynyloxybenzoylamino)methyl]-2-(4-methanesulphonylpiperazin-1-yl)malonate in 4 ml of tetrahydrofuran and 1 ml of methanol. The reaction medium is stirred at ambient temperature for 48 h then hydrolysed, diluted with ethyl acetate and brought to pH=6 with an aqueous solution of hydrochloric acid having a concentration of 1N. After extraction with ethyl acetate, the organic phase is washed with water then with a saturated aqueous solution of sodium chloride. After drying over magnesium sulphate and filtering, the solvent is concentrated under vacuum. The crude product obtained is purified by recrystallization in ethyl acetate. 30 mg (32%) of 3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:38])([F:37])[C:13]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][C:13]([OH:31])([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([F:37])([F:11])[F:38])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH:27]([NH2:29])[CH3:28])[CH:23]=[C:24]([F:26])[CH:25]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:29][CH:27]([C:22]2[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[CH:21]=2)[CH3:28])=[CH:13][CH:14]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Yield: 94.8 %

Procedure:
Following a similar procedure to that described in Example (1a), 2.0 g of 4-chlorophenyl 3-nitrophenyl ketone, 2.40 g of 1-(3,5-difluorophenyl)ethylamine, 4.26 ml of triethylamine, 1.01 ml of titanium tetrachloride, 3.02 g of sodium cyanoborohydride and 0.66 ml of acetic acid were reacted, to obtain 2.92 g of the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc(Cl)c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.00 (br s, 2H), 8.98 (s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.28 (s, 1H), 8.20 (dd, J=8.5, 2.3 Hz, 1H), 7.85 (t, J=1.9 Hz, 1H), 7.81-7.75 (m, 2H), 7.55 (t, J=7.9 Hz, 1H), 7.49 (ddd, J=8.0, 2.0, 1.0 Hz, 1H).
Reaction SMILES: ClC1C(O)=CC=CN=1.ClC1C=CC(Cl)=CC=1[N+]([O-])=O.[OH-].[K+].[Cl:22][C:23]1[C:28]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[N+:37]([O-])=O)=[CH:27][CH:26]=[CH:25][N:24]=1>O.O1CCOCC1.[Ni]>[Cl:22][C:23]1[C:28]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[NH2:37])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Oc1cccnc1Cl
Agent: [Ni]
Agent: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: Oc1cccnc1Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)ccc1Oc1cccnc1Cl
Yield: 65.1 %

Procedure:
The starting 2-chloro-3-(2'-amino-4'-chlorophenoxy)-pyridine of the formula (400) is prepared as follows: With stirring, a mixture of 25.9 g (0.2 mole) of 2-chloro-3-hydroxypyridine and 38.4 g (0.2 mole) of 2,5-dichloronitrobenzene is heated to 120°-125° C. and to this mixture is added a solution of 13.17 g of solid 85% potassium hydroxide in 10 ml of water in the course of 2 hours. The hot suspension is mixed in a mixer with 300 ml of water. The crystalline precipitate is collected by filtration and washed with 1000 ml of water. A solution of 14.25 g (0.05 mole) of the resultant 2-chloro-3-(2-nitro-4-chlorophenoxy)-pyridine in 75 ml of dioxane is then hydrogenated in the presence of 15 g of Raney nickel. The catalyst is then removed by filtration, the filtrate is distilled and the precipitated crystalline product is collected by filtration and dried, affording 8.3 g of 2-chloro-3-(2'-amino-4'-chlorophenoxy)-pyridine of the formula (400) with a boiling point of 163°-167° C./50.76 kPa.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1.[NH2:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:23][C:24]1[C:25]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)n1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2NC(=O)c2nc(Br)c(F)cc2N)n1
Yield: 15 %

Procedure:
Method 27 was followed using tert-butyl 6-(3-aminopyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate (1.0 equiv.), 3-amino-6-bromo-5-fluoropicolinic acid (1.0 equiv.), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in DMF yielding tert-butyl 6-(3-(3-amino-6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate in 15% yield. LCMS (m/z): 520.1 (MH+); LC Rt=3.4 min.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]5[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=5)[N:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH2:26][CH2:27][C:28]5[N:29]([C:31]([C:34]([F:35])([F:36])[F:37])=[N:32][N:33]=5)[N:30]=4)[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Methanol (375.0 mL) was added to 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (25.0 g, 48 m mol) in a 2.0 L autoclave reactor and to this was added 10% Pd/C (12.5 g, 50% w/w) paste at 22-25° C. under nitrogen gas atmosphere. The reaction was performed under hydrogen pressure (5.0 bar) at 50° C. temperature for 10.0 h. The reaction mass was cooled to room temperature and the catalyst removed by filtration. Filtered cake was washed with methanol. The solvent was evaporated and the residue was azeotropically distilled by is ethylacetate (2×125.0 mL) at 40° C. under reduced pressure to 3.0 rel vol (75.0 mL). Drop wise addition of tert-butylmethylether (MTBE, 375.0 mL) to the reaction mass resulted in solid material, which was collected by filtration and washed with MTBE (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (22.3 g, 88%) as a white color free flowing solid. The isolated material was confirmed by XRPD as Form A.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].C(N(CC)CC)C.[CH2:14]([NH:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].Cl>COC1CCCC1>[CH2:14]([N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:2](=[O:3])[O:4][CH2:5][Cl:6])[CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)OCCl
Reactant: CCCCNCCCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COC1CCCC1
Product: CCCCN(CCCC)C(=O)OCCl
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Chloromethyl chloroformate (5.0 ml) was added dropwise to 100 ml of a solution of 11.7 ml of triethylamine and 11.3 ml of N,N-di-n-butylamine in cyclopentyl methyl ether under ice cooling, and the mixture was stirred at room temperature for 13 hr. 2 N hydrochloric acid (100 ml) was added thereto, followed by separation. The organic layer was washed with 100 ml of a 5% aqueous sodium hydrogencarbonate solution and 100 ml of semi-saturated brine, was dried over anhydrous magnesium sulfate, and was filtered, and the solvent was removed by distillation under the reduced pressure to give 12.7 g of chloromethyl N,N-di-n-butylcarbamate.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine (2.33 g) in dry DCM (120 ml, TEA (4.2 ml 2.5 eq), BOC2O (6.1 g, 2.3 eq.), DMAP (296 mg, 0.2 eq.) were added. The mixture was stirred at rt. for 1 h then the solvent was evaporated in vacuo. The material thus obtained was purified by flash chromatography over silica gel (eluting with 20% ethyl acetate in hexane) to give the title compound (3.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1>>[NH2:37][C:34]1[S:35][CH:36]=[C:32]([CH2:31][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])[N:33]=1
Reactant: Nc1nc(CCl)cs1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: Nc1nc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)cs1

Procedure:
(5Z)-3-[(2-Amino-1,3-thiazol-4-yl)methyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 4-chloromethylthiazol-2-ylamine following General Procedure H.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)=[O:13]>CCOCC.CO>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2n[nH]c3ccc(Br)cc23)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(NCC1CCNCC1)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
2M HCl in Et2O (1.8 L) was added to a solution of compound tert-butyl 4-(aminomethyl)piperidine-1-carboxylate 11a (0.24 moles) in MeOH (500 mL). The mixture was stirred for 3 hours at room temperature then the resulting solid was filtered and dried to give 5-Bromo-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamide hydrochloride 11 b (76% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(S(=O)(=O)NC(=O)CCC(=O)O)cc2)nn1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (0.10 g, 0.25 mmol) and THF (10 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (0.28 mL, 1.0 M solution in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then succinic anhydride (28 mg in 5 mL THF, 0.28 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. A few drops of acetic acid was added, then the mixture was concentrated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/8:2) to afford the desired product (39 mg, 31%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (d, 2H), 7.63 (m, 1H), 7.42 (d, 2H), 7.15 (t, 2H), 2.41 (br s, 4H); MS (ESI) m/z: 493 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[NH:23][C:22](=[O:24])[CH2:21][N:9]2[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[NH:23][C:22](=[O:24])[CH2:21][N:9]2[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2
Yield: 88.8 %

Procedure:
A solution of intermediate 4, 6-benzyloxy-2,5-dioxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid ethyl ester, (0.770 g, 2.34 mmol) in trifluoroacetic acid (20 ml) was stirred at 25° C. for 1 h. The solvent was then evaporated under reduced pressure and residual trifluoroacetic acid removed by azeotropic distillation with toluene in vacuo. Acetic acid (5 ml) was added and the mixture subjected to azeotropic distillation with toluene in vacuo to remove solvent and residual acid. Recrystallization of the solid residue from ethyl acetate gave 0.497 g (88% yield) of the title ester as white crystals; mp 265° C. (dec).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:9]2[S:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:26][C:8]=2[C:7]=1[OH:33])=[O:5])C.[NH2:34][CH2:35][C:36]([OH:38])=[O:37]>C[O-].[Na+].CO>[OH:33][C:7]1[C:8]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:24][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:14][CH:13]=2)=[N:11][C:6]=1[C:4]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)cc2)c2sc(-c3ccccc3)nc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccc(N3CCOCC3)cc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A mixture of 7-Hydroxy-4-(4-morpholin-4-yl-phenyl)-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (56 mg, 0.12 mmole) and glycine (182 mg, 2.43 mmole) in 0.5 M sodium methoxide/methanol (4.4 ml) was refluxed for 5 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (120 ml) and extracted with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (5 ml). The resulting suspension was extracted with ethyl acetate, washed with brine and dried in vacuo to give the title compound as a yellow solid (44 mg). 1H NMR (DMSO-d6, 200 MHz): δ=13.1 (br s, 1H), 9.37 (t, 1H), 8.15 (m, 2H), 8.04 (m, 2H), 7.62 (m, 3H), 7.10 (m, 2H), 4.06 (d, 2H, J=5.8 Hz), 3.77 (m, 4H); MS: (+) m/z 491.22 (M+1).
Reaction SMILES: C([C@H]1[O:9][C:8](=[O:10])[C@:7]([C:17]2[CH2:21][CH2:20][CH2:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)(C)(C)C.CO.O.[OH-].[K+].[Cl-].[NH4+]>>[C:17]1([C@:7]([OH:6])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](C2=CCCC2)(c2ccccc2)O1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C(O)[C@](O)(C1=CCCC1)c1ccccc1
Temperature: 130 °C
Yield: 69.9 %

Procedure:
Intermediate (1c) (540 mg, 1.9 mmol) was dissolved in MeOH (927 μL, 22.9 mmol). Water (1.84 mL, 102 mmol) was added, followed by the addition of KOH (1.1 g, 18.8 mmol). The mixture was refluxed at 130° C. for 3 hours, followed by dilution to 250 mL with saturated ammonium chloride, then washed (2×100 mL hexane). The remaining aqueous emulsion was washed (2×250 mL EtOAc). The EtOAc layers were combined, washed with 50 mL saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to yield intermediate (1d) as a brownish-yellow solid (290 mg).
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.O.[CH2:26](O)[CH3:27]>>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]([O:23][CH2:26][CH3:27])=[O:22])=[CH:16][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCO
Reactant: CCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCc1cc2cc(C(=O)OCC)ccc2[nH]1

Procedure:
A solution of 2-(n-undecyl)indole-5-carboxylic acid (15.0 g) in ethanol (50 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml of strength 34% w/v) was refluxed for 3 hours. The solution was poured onto a mixture of crushed ice and water and the precipitated solid was collected. Recrystallisation from ethanol (100 ml) with charcoal treatment gave ethyl 2-(undecyl)indole-5-carboxylate (7.5 g), in the form of white crystals, m.p. 76°-77° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[NH2:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:17])[CH3:16]
Reactant: NCC1(Nc2ccccc2)CCCCC1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.8 %

Procedure:
580 mg (1.94 mmol) of 2-bromo-N-(2,6-diisopropylphenyl)acetamide are added to 400 mg (1.96 mmol) of (1-aminomethylcyclohexyl)phenylamine (obtained in Example 2/b) in 20 ml of dimethylformamide. The reaction medium is stirred at room temperature for 48 h. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 60/40, v/v). 309 mg of N-(2,6-diisopropylphenyl)-2-[(1-phenylamino-cyclohexylmethyl)amino]acetamide are obtained in the form of a yellowish oil. Yield=37%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[NH2:19][C:20]([CH:24]1[CH2:26][CH2:25]1)([CH3:23])[C:21]#[N:22]>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:19][C:20]([C:21]#[N:22])([CH:24]1[CH2:26][CH2:25]1)[CH3:23])=[O:7]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CC(N)(C#N)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C#N)(NC(=O)c1cccc(CCl)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
3-(Chloromethyl)benzoyl chloride (9.08 mmol, 1.290 ml, 1.716 g) and triethylamine (27.2 mmol, 3.79 mL, 2.76 g) were stirred in dichloromethane (10 mL) at 0° C. 2-Amino-2-cyclopropylpropanenitrile (9.08 mmol, 1 g) was added dropwise and the reaction allowed to warm to room temperature and stir for 1 hour. The reaction mixture was washed with water and the organic phase concentrated under vacuum to afford the title compound (1.451 g). MS (ESI) m/z 263.1 [M+H]+
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=1)[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]3[S:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[CH:25]=3)[CH:23]=1)[NH:20][N:19]=[CH:18]2)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][N:14]([C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]3[S:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[CH:25]=3)[CH:23]=1)[NH:20][N:19]=[CH:18]2)[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=1
Reactant: Nc1nccc(N(CCCNC(=O)OCc2ccccc2)c2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: NCCCN(c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 16.4 %

Procedure:
A solution of {3-[(2-amino-pyrimidin-4-yl)-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-amino]-propyl}-carbamic acid benzyl ester (prepared from Example #F.8.1 using general procedures O and N, 0.169 g, 0.308 mmol) and formic acid (0.116 mL, 3.08 mmol) in methanol (2 mL) was added dropwise to a suspension of Palladium black (0.080 g, 0.752 mmol) in methanol (1.5 mL). The resulting mixture was allowed to stir at ambient temperature for about 19 hours. The resulting suspension was filtered though celite and the solvent was removed under reduced pressure. The resulting crude product was purified by reverse chromatography (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% acetonitrile/0.1 M aqueous ammonium acetate −100% acetonitrile over 20 min, 100% acetonitrile hold 5 minutes, 21 mL/min) to afford N4-(3-amino-propyl)-N4-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-pyrimidine-2,4-diamine (0.021 g, 17% yield) as a green solid. RP-HPLC (Table 1, Method e) Rt 1.62 min.; m/z: (M+H)+ 416.1.