Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:9][N:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]2([CH3:20])[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:22]1([NH:21][C:8]([O:9][N:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH:13]([O:18][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:18][CH:13]3[CH2:12][C:11]([CH3:19])([CH3:20])[N:10]([O:9][C:8](=[N:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:15]([CH3:17])([CH3:16])[CH2:14]3)=[O:38])[CH2:14][C:15]2([CH3:16])[CH3:17])=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC(=NC1CCCCC1)NC1CCCCC1
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC(=NC3CCCCC3)NC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.3 %

Procedure:
To a solution of 1,3-dicyclohexyl-2-(4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-yl)-isourea [compound 8 prepared according to Example 8] (8.35 g, 22 mmol) and 4-dimethylaminopyridine (160 mg) in pyridine (20 ml) is added sebacoylchloride (2.5 g, 10.5 mmol). The mixture is stirred at room temperature for 22 hours and then diluted with ice-water (250 ml). The precipitate is filtered off, washed with water and dried to afford 9.75 g of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:15][O:14][C:13]2[CH:16]=[C:17]3[C:21](=[CH:22][C:12]1=2)[CH2:20][CH2:19][O:18]3.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.ClCC1C=NC(OC)=NC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1)[C:8](=[O:11])[C:7]12[C:12]2=[CH:22][C:21]3[CH2:20][CH2:19][O:18][C:17]=3[CH:16]=[C:13]2[O:14][CH2:15]1
Reactant: O=C1Nc2c(Cl)cccc2C12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using 7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, 7′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one was obtained (30%) as a colorless solid: mp 210-211° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.34-7.31 (m, 1H), 7.21-7.16 (m, 2H), 7.10-7.05 (m, 1H), 6.67-6.65 (m, 1H), 6.49 (s, 1H), 6.43 (s, 1H), 5.34 (s, 2H), 4.85 (d, J=9.6 Hz, 1H), 4.74 (d, J=9.6 Hz, 1H), 4.57-4.48 (m, 2H), 2.94 (t, J=3.0 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.4, 161.2, 160.4, 154.1, 139.4, 138.9, 137.2, 135.4, 130.5, 124.6, 122.8, 120.6, 120.1, 119.9, 118.7, 117.1, 114.3, 114.2, 108.7, 92.4, 79.8, 72.0, 56.6, 28.1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)CCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
Into a suspension of methyl 4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]4-oxobutanoate (250 mg, 0.48 mmol) in THF/H2O (2/1) (10 mL) was added NaOH (1.0 N, 2.4 mL). The resulting solution was stirred at rt for 1.5 hr and quenched with HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration, washing with water (2×5 mL) and drying under vacuo at 70° C. for 20 hrs gave the title compound as a yellow powder (83 mg, 34%) in 99.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:15]C([O-])(C)C.[K+].CI>CN(C)C(=O)C>[F:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]2[N:6]([CH3:15])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cc2c(cc1F)OCC(=O)N2
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CN1C(=O)COc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile (CAS Reg. No. [151982-49-9], 4.71 g) in N,N-dimethylacetamide (108 ml) were added KOtBu (3.08 g) and methyl iodide (3.83 g). The mixture was stirred at room temperature for 3.5 h. Ice water was added. The suspension was filtered and the solid was washed with water and dried to give the title compound (4.07 g) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=4)[C:23](=[O:34])[CH2:22]3)[CH:17]([CH3:35])[CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:34][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH:21]([N:18]2[CH2:19][CH2:20][N:15]([C:2]3([CH3:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH2:16][C@@H:17]2[CH3:35])[CH2:22]1
Reactant: CC1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CC(=O)c2cc(C(F)(F)F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CC(O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-methyl-4-{3-methyl-4-[3-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidine-1-carboxylate (100 mg, 0.202 mmol) in ethanol (7 mL) was added sodium borohydride (57 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, and the residue was quenched with 10 mL of 1 N aqueous NaOH solution and 10 mL of EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc twice (2×15 mL). The combined extracts were washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give the desired product which was directly used for the next step (93 mg, 92%). LC-MS [M+1]=498.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].CC([O-])(C)C.[K+].[Br-].[Li+]>C1(C)C=CC=CC=1>[CH2:9]([N:11]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCNCC
Reactant: Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(C)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
20 mmol of p-chlorotoluene (2.53 g), 24 mmol of diethylamine (1.75 g), 28 mmol of KOtBu (3.13 g), 4 mmol of lithium bromide (0.35 g) and 44 mg of trans-di-μ-acetatobis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipalladium(II) (0.3 mol %) are suspended in 50 ml of toluene and refluxed for 24 hours. After cooling to room temperature, the salts are filtered off and washed with petroleum ether. The solvents are removed from the filtrate on a rotary evaporator. Distillation via a bulb tube (100° C./12 torr) gives 4-(N,N-diethylamino)toluene as a colorless liquid in a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH:33]6[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]6)[N:29]=5)[C:25]=4[S:46][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:46][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(C4CCNCC4)cc3-5)cc2Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 4-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]piperidine-1-carboxylate 1.2 g (1.8 mmol, 1 eq) in DCM (40 mL) was added trifluoroacetic acid (4.2 mL, 30 eq). The reaction mixture was stirred at rt for 3 h. The Volatile material was evaporated and the residue was diluted with EtOAc. Sat. Na2CO3 was added until pH about 7. The layers were separated and the aqueous layer was extracted with EtOAc (3 times) and the combined organic layers were concentrated to give a brown solid (1 g, quantitative). 1H-NMR (DMSO-d6) δ 8.41 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.74 (d, 1H), 7.47 (m, 2H), 7.30 (m, 2H), 7.20 (m, 2H), 5.24 (s, 2H), 4.25 (m, 1H), 3.40 (t, 2H), 3.18 (m, 2H), 2.93 (t, 2H), 2.76 (t, 2H), 2.05 (m, 2H), 1.91 (m, 2H). LCMS RT=2.83 min; [M+H]+=561.2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](OB(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[F:22].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:17][C:16]=1[F:22]
Reactant: Fc1cc(I)ccc1Br
Reactant: CCCc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCCc1ccc(-c2ccc(Br)c(F)c2)cc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 16.5 g of 4-propylphenylboric acid as dissolved in 130 ml of ethanol was dropwise added to a mixture comprising 30 g of 1-bromo-2-fluoro-4-iodobenzene, 1.6 g of tetrakistriphenylphosphine palladium(O), 186 ml of benzene and 140 ml of 2M aqueous sodium carbonate solution, in nitrogen atmosphere at room temperature. The reaction solution was then refluxed for 5 hours, cooled to room temperature, extracted with chloroform and washed three times with water, and chloroform was removed by distillation. The residue formed was distilled under reduced pressure (b.p. 155° to 170° C./3 mmHg) to obtain 11.7 g of 4-bromo-3-fluoro-4'-propylbiphenyl.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH:14]([F:16])[F:15])[CH:13]=1)(C)(C)C.Cl.CCO>C(OCC)(=O)C>[F:15][CH:14]([F:16])[C:12]1[CH:13]=[C:8]([NH2:7])[CH:9]=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cncc(C(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5-Difluoromethyl-pyridin-3-yl)-carbamic acid tert-butyl ester (0.30 g, 1.2 mmol) was dissolved in 10 ml ethyl acetate and 8M HCl in EtOH (3 ml, 25 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by addition of 20 ml sat. NaHCO3 solution and extracted three time with 50 ml ethyl acetate. The organic phases were pooled, dried with sodium sulfate and evaporated. The title compound was obtained as a brown oil (0.158 g, 89%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:43][O:44][CH2:45][CH2:46][NH2:47]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:47][CH2:46][CH2:45][O:44][CH3:43])=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: COCCN
Product: COCCNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 2-methoxyethanamine
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:29])[C:14]([C:15]([NH:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]3)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:30])[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:29])[C:14]([C:15]([NH:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:30])[CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2c(C)nn3c(OCc4c(F)cccc4F)cc(C)cc23)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC[C@H]3CC[C@H](C(=O)O)CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
90 mg (0.19 mmol, 1.0 eq.) of methyl trans-4-{[({7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]methyl}cyclohexanecarboxylate from Example 35 were dissolved in 5.5 ml of THF/methanol (5/1) and admixed with 1.3 ml of 1 N aqueous lithium hydroxide solution. The mixture was stirred at RT for 3 days. Subsequently, another 2 ml of 1 N lithium hydroxide solution were added and the mixture was stirred at 60° C. for 7 days. After cooling, the mixture was acidified to pH=3 with 1 N hydrochloric acid and freed of the organic solvents on a rotary evaporator. The resulting aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed with water, then dried with sodium sulphate, filtered and concentrated. The residue was purified by means of thick-layer chromatography (eluent:dichloromethane/methanol=20/1). 46 mg of the target compound were obtained (53% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:26][C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=Cc1cccnc1
Product: CN(Cc1cccnc1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 71 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with pyridine-3-carbaldehyde using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyridin-3-ylmethyl-amine as a solid (71% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 427 as a solid (99% yield). NMR (CDCl3, 400 MHz), 2.34 (3H, s), 3.67 (2H, s), 3.88 (2H, s), 3.92 (4H, t, J=5.2), 4.06 (4H, t, J=5.2), 5.25 (2H, s), 7.30-7.33 (2H, m), 7.73-7.75 (2H, m), 8.55-8.57 (1H, m), 8.66-8.67 (1H, m), 9.30 (2H, s). MS: (ESI+): MH+=449
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:20]=[C:19]([Cl:21])[S:18][C:17]=1[Cl:22].O>CN(C=O)C.C1COCC1>[Cl:22][C:17]1[S:18][C:19]([Cl:21])=[CH:20][C:16]=1[CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1cc(CBr)c(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1cc(Cl)sc1Cl)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a stirred solution of sodium hydride (60% oil dispersion, 7.6 g, 190 mmol) in DMF (32 mL) was added a solution of diethyl malonate (35.2 g, 220 mmol) in THF (120 mL) at 0° C. and the mixture was stirred for 30 min at 0° C. To the mixture was added a solution of 3-(bromomethyl)-2,5-dichlorothiophene (26.9 g, 110 mmol) in THF (50 mL) at -35° C. over 1.5 hours. After stirring at -35° C. for 2 hours, the reaction mixture was poured into water and the whole extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. Fractionally distillation of the residue under reduced pressure (bp 150° C., 1.0 mmHg) provided the subtitle compound (28.6 g, 80% yield).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12](=O)[N:11]2[CH:16]=[CH:17][NH:18][C:10]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:12]1[N:11]2[CH:16]=[CH:17][N:18]=[C:10]2[C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)c1ccc(=O)n2cc[nH]c12
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cl)n2ccnc12
Yield: 87.5 %

Procedure:
1.0 g (4.20 mmol) of 8-Benzoylimidazo[1,2-a]pyridin-5(1H)-one (example L, step 2) and 20.0 g (130.44 mmol) of phosphoric trichloride are dissolved in 20 ml toluene and refluxed for 1 h. The solvent is evaporated under vacuum; the crude is dissolved in 200 ml ethyl acetate and extracted with 100 ml saturated sodium hydrogen carbonate solution and 100 ml water. The organic phase is dried over magnesium sulfate, filtrated and concentrated. Petrolether is added to the residue and the precipitate is filtrated to yield 943 mg (87.5% of th.) (5-Chloroimidazo[1,2-a]-pyridin-8-yl)(phenyl)methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Yield: 88.7 %

Procedure:
To a solution of methyl 2-methoxy-5-aminobenzoate (300 mg) and dry pyridine (3 ml), methanesulfonyl chloride (210 mg) is added dropwise with ice cooling and stirring, and the resultant mixture is stirred at room temperature for 1 hour. The reaction mixture is acidified with 6 N hydrochloric acid and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to remove the methylene chloride. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride-2% methanol/methylene chloride, and the eluate is evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/isopropyl ether to give methyl 2-methoxy-5-methanesulfonamidobenzoate (381 mg) as colorless prisms melting at 84° to 86° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C:13](=O)([O-])[O-:14].[K+].[K+]>CO.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:14][CH3:13])[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCc1cccc(C(=O)OC)c1
Temperature: 55 °C
Yield: 100.8 %

Procedure:
A mixture of 3-bromomethyl-benzoic acid methyl ester (556 mg, 2.4 mmol) and potassium carbonate (670 mg, 4.9 mmol) in methanol (10 ml) and tetrathydrofuran (10 ml) was heated at 55° C. for 2 h. After cooling, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. After drying in vacuo, 3-methoxymethyl-benzoic acid methyl ester (436 mg, quantitative) was isolated as a white solid. 1H NMR (CDCl3), δ (ppm): 8.01 (s, 1H), 7.98 (d, 1H), 7.55 (d, 1H), 7.43 (t, 1H), 4.50 (s, 2H), 3.92 (s, 3H), 3.41 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40](NC2C=CN(C)N=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:55][C:56]1[CH:60]=[CH:59][N:58]([C:61](=[O:67])[CH2:62][C:63]([OH:66])([CH3:65])[CH3:64])[N:57]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:55][C:56]2[CH:60]=[CH:59][N:58]([C:61](=[O:67])[CH2:62][C:63]([OH:66])([CH3:65])[CH3:64])[N:57]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)(O)CC(=O)n1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)CC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
Triphenylphosphine (186 mg, 0.71 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (143 mg, 0.81 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 157 mg, 0.47 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The reaction was chilled to 0° C. and the combined solution of 1-(3-amino-pyrazol-1-yl)-3-hydroxy-3-methyl-butan-1-one (87 mg, 0.47 mmol) and 2,6-lutidine (0.165 mL, 1.42 mmol) in methylene chloride (4 mL) was added. The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 40% ethyl acetate/hexanes) eluted the desired product and an impurity simultaneously. Further purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyryl)-1H-pyrazol-3-yl]-propionamide (28 mg, 12%) as a white powder: ESI-LRMS m/e calcd for C23H30ClN3O5S [M+] 495.2, found 496.2 [M+H+], 478.0 [M−H2O+H+], 396.0 [M−COCH2C(CH3)2OH]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.23 (m, 2H, CH2), 1.37 (s, 6H, 2×CH3), 1.44-1.98 (m, 8H, 4×CH2), 2.09-2.32 (m, 1H, CH), 3.23 (AB, Jgem=17.4 Hz, 2H, CH2), 3.27 (s, 3H, SO2CH3), 3.64 (t, J=7.5 Hz, 1H, CH), 7.02 (d, J=2.9 Hz, 1 H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz, 1H, Ar), 8.14 (d, J=2.9 Hz, 1H, Ar), 8.46 (s, 1H, NH).