Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[CH3:44][O:43][C:41](=[O:42])[CH2:40][NH:1][C@@H:2]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-2-amino-1-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-3,3-diphenylpropane (8.6 g, Example 1i) and anhydrous K2CO3 (13.0 g)in dimethylformamide (50 ml) was added methyl bromoacetate (4.5 ml). The reaction was stirred at room temperature for 0.75 h then diluted with ethyl acetate (200 ml) and washed with water (4×100 ml), brine (100 ml), dried over MgSO4 and evaporated to dryness. The residual oil was purified on silica gel eluting with petroleum ether-ethyl acetate mixtures to give (S)-N-(1-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-3,3-diphenylprop-2-yl)glycine methyl ester as an oil (7.61 g) 1H NMR (360 MHz, CDCl3) δ7.77 (1H, s), 7.71 (2H, s), 7.42 (2H, d, J=7.4 Hz), 7.33-7.13 (8H, m), 4.44 (2H, s), 4.12 (1H, d, J=7.2 Hz), 3.73-3.69 (1H, m), 3.63 (3H, s), 3.57-3.52 (1H, m), 3.53 (2H, d, J=6.7 Hz) and 3.44-3.36 (1H, m).
Reaction SMILES: [CH3:1][CH:2]([CH2:28][CH3:29])[C:3]([O:5][CH:6]1[CH:15]2[C:10]([CH:11]=[CH:12][CH:13]([CH3:26])[CH:14]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH:20]([OH:25])[O:19]2)=[CH:9][CH:8]([CH3:27])[CH2:7]1)=[O:4].[C:30](=O)(O)[O-].[Na+]>CO.C(Cl)(=O)C>[CH3:1][CH:2]([CH2:28][CH3:29])[C:3]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:26])[C:14]=2[CH2:16][CH2:17][CH:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH:20]([O:25][CH3:30])[O:19]2)[CH:9]=[C:8]([CH3:27])[CH:7]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(O)O3)C21
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCC(C)C(=O)Oc1cc(C)cc2ccc(C)c(CCC3CC(O)CC(OC)O3)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 393.1 %

Procedure:
Acetyl chloride (200 μL, 2.8 mmol) was added to a stirred solution of hemiacetals II (19.0 g, 46.7 mmol) in methanol (100 ml). The solution was stirred for 15 min at ambient temperature. Sodium bicarbonate (1.0 g) was added and the mixture was stirred for another 15 min. The mixture was filtered through a pad of Celite (5.5×1 cm) and washed with toluene. Evaporation of solvent of the filtrate gave crude acetals III (19.4 g, yield 98%) as a colorless syrup (HPLC purity >95%). This was used without further purification in the next step.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])=[CH:25][CH:24]=1.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([CH2:53][NH2:54])[N:52]=1)([CH3:47])[CH3:46]>>[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39]([NH:54][CH2:53][C:51]4[N:52]=[C:48]([CH:45]([CH3:47])[CH3:46])[S:49][CH:50]=4)=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])=[CH:25][CH:24]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: CC(C)c1nc(CN)cs1
Agent: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1csc(C(C)C)n1
Yield: 68 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (2-isopropylthiazol-4-yl)methanamine, the title compound was obtained as a colourless solid in 68% yield: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (t, J=5.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.19-7.14 (m, 3H), 4.41-4.39 (m, 4H), 3.97 (t, J=9.0 Hz, 2H), 3.42 (t, J=9.0 Hz, 2H), 3.26-3.15 (m, 1H), 2.44 (s, 3H), 1.28 (d, J=6.0 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 163.6, 162.2, 160.4, 157.9, 155.5, 154.0, 133.0 (d), 130.4 (d), 118.4, 115.9, 113.8, 46.6, 42.4, 42.0, 32.9, 23.3, 17.5; MS (ES+) m/z 474.0 (M+1).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:16]=[C:17]([CH:21](Cl)[CH3:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]>O>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:16]=[C:17]([CH:21]([C:1]#[N:2])[CH3:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: CC(Cl)c1cccc(C(=O)c2cccs2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C#N)c1cccc(C(=O)c2cccs2)c1

Procedure:
To a stirred and hot mixture of 2.7 parts of sodium cyanide in 20 parts of dimethylsulfoxide is added dropwise a solution of 5.8 parts of α-chloro-α-methyl-m-tolyl 2-thienyl ketone in 10 parts of dimethylsulfoxide at 60° C. Another 5 parts of dimethylsulfoxide is added and the whole is stirred for 2.5 hours at 50°-55° C. The reaction mixture is poured onto 35 parts of water and the product is extracted with ether and ethyl acetate. The combined organic layers are washed with water, dried, filtered and evaporated in vacuo. The residue is dissolved in benzene. This solution is washed with water, dried and evaporated in vacuo, yielding m-(2-thenoyl)hydratroponitrile, also named α-cyano-α-methyl-m-tolyl 2-thienyl ketone, as a residue.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.13 g (0.0005 mole) of 2-chloro-9-cyclopentyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-10), 1 mL of N,N-dimethylacetamide and 0.047 mL (0.00075 mole) of iodomethane at 0 degrees was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.135 g of 2-chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-10) as an yellow solid.
Reaction SMILES: [N:1]1([C:10]2[S:11][C:12](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.O1CCCC1.[H][H]>[C].[Pd].C(O)C>[N:1]1([C:10]2[S:11][C:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1sc(-n2cnc3ccccc32)nc1C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1sc(-n2cnc3ccccc32)nc1C(C)C
Yield: 99.4 %

Procedure:
A mixture of ethyl (2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoate (1.50 g), 5% palladium-carbon (1.0 g), tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred at room temperature under an atmospheric pressure of hydrogen for 14 hrs. The catalyst was removed by filtration, and the organic layer was concentrated to give ethyl 3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propionate (1.50 g, 99%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[O:20][CH3:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1ccc(/C=C/C(=O)O)c(OC)c1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c(OC)c1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=0.97 min; [M+H]+=396.15.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18](Cl)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18]([N:35]3[CH2:36][CH2:37][CH:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34]3)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)nc21
Yield: 85.7 %

Procedure:
Following the procedure of Example X-2, the reaction of 3-benzyloxy-7-chloro-1-ethyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example N-2, 200 mg, 0.572 mmol) with 3-(N-tert-butoxycarbonylamino)pyrrolidine (117 mg, 0.629 mmol) in dichloromethane (5 mL) in the presence of triethylamine (0.087 mL) afforded 245 mg of the title compound as a solid, mp 157-159° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:15]=1.O>O1CCOCC1>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][C:18]1[CH:19]=[CH:14][N:15]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:17]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(Oc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a suspension of NaH (0.006 mol) in 1,4-dioxane (30 ml), 2,4,6-trimethyl-phenol (0.006 mol) was added. The mixture was stirred for 15 minutes at room temperature, and a clear solution formed. 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.004 mol) was added, and the reaction mixture was heated to reflux under Argon for 15 hours. The reaction mixture was allowed to cool to room temperature, 0.5 ml of water was added, followed by 4 g of silica gel, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH 100:0:0 to 97:3). The pure fractions were collected and the solvent was evaporated, yielding 1.18 g (89.4%) of 4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (comp. 20).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[OH-].[Na+].C1COCC1>CN(C=O)C>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(COc2ccccc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Yield: 23.4 %

Procedure:
A mixture of 5.0 g (0.025 mol) 4-phenoxymethylphenol, 5.35 g (0.025 mol) 2-chloromethylquinoline hydrochloride and 30 ml (2N, NaOH) in 50 ml DMF and 100 ml THF was stirred at 60° C. bath temperature for a period of 3 hours. The reaction mixture was poured into wast and extracted with ether. The ether extract was washed with water, dried and concentrated to dryness to obtain solid. Recrystallization from acetonitrile yielded (2.0 g) product, m.p. 100°-111° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)=[O:21]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CN1CC=C(c2c[nH]c3ccncc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)5-azaindole (20 mg, 0.094 mmol), 2,6-dichlorobenzoyl chloride (27 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33](OC)[CH:32]=4)=[CH:27][CH:26]=3)[C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[CH3:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:45][CH:46]=1.O.C(#N)C.O.C1C[O:59][CH2:58]C1>O.O.O.S(C1C=CC(C)=CC=1)(O)(=O)=O.N[C@@H](CC1C=CC(C2C=C(O[C@H](C3C=CC(C4C=CC=C(OC)C=4)=CC=3)C(F)(F)F)N=C(N)N=2)=CC=1)C(O)=O>[OH2:4].[OH2:48].[S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:40])=[CH:42][CH:43]=1)([OH:50])(=[O:49])=[O:48].[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][C:30]=3[O:59][CH3:58])[C:21]([F:22])([F:23])[F:24])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: COc1cccc(-c2ccc([C@@H](Oc3cc(-c4ccc(C[C@H](N)C(=O)[O-])cc4)nc(N)n3)C(F)(F)F)cc2)c1
Reactant: C1CCOC1
Agent: COc1cccc(-c2ccc([C@@H](Oc3cc(-c4ccc(C[C@H](N)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1cc(-c2ccccc2)ccc1[C@@H](Oc1cc(-c2ccc(C[C@H](N)C(=O)O)cc2)nc(N)n1)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate (120.0 g, 88 w %, 105.6 g active, 196 mmol) was added to a solution of TsOH.H2O (39.8 g, 209 mmol) in a mixture of THF (240 mL) and water (48 mL). The mixture was heated to 50° C. to give a homogeneous solution. Approximately 120 mL of a mixture of ACN/water (1200/60 mL) was added and the mixture was seeded with (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate tosylate dihydrate (0.63 g). After aging for 1 hour at 40° C., a nice slurry was obtained. The remaining ACN/water mixture was added slowly over 3 hours at 40° C. and the slurry was aged at 40° C. for 2 hours then slowly cooled to 20° C. and aged overnight. The solid was collected by filtration and the filter cake was washed with 5/1 ACN/THF with ˜5 vol % water (500 mL). Air drying at room temperature overnight gave 138.5 g of the product as a white solid (99.5 A %, 93.4% yield corrected for purity). Loss in the mother liquor and wash was 6.5%. KF of solid was 4.4%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]=[C:11]=[O:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.ClCCl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=Nc1c(F)cc(Cl)cc1Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2c(F)cc(Cl)cc2Br)CC1

Procedure:
1-Bromo-5-chloro-3-fluoro-2-isocyanatobenzene (D6) (4.4 mmol, 1.1 g) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 4.4 mmol, 0.88 g) were mixed together. Dichloromethane (5 ml) was added to the mixture at room temperature for 1 hour. THF (5 ul) was added at room temperature for one hour. Solvent was subsequently evaporated and the crude obtained was purified by chromatography to afford the title compound, 0.6 g, 30%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1)(=[O:24])=[O:23])([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[CH:29][CH:28]=1)(=[O:23])=[O:24])([O-:15])=[O:14]
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C1CCc2cccc(F)c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccc(F)c3C2)cc1)Cc1ccccn1
Yield: 91.9 %

Procedure:
Following General Procedure B: Reaction of 8-fluoro-2-tetralone (159 mg, 0.97 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (400 mg, 0.97 mmol) and NaBH(OAc)3 (411 mg, 1.9 mmol) in a mixture of CH2Cl2 (10 mL) and acetic acid (0.2 mL) for 18 hours followed by purification of the crude material by column chromatography on silica gel (CHCl3/MeOH/NH4OH 20:2:1) afforded the title compound (500 mg, 92%) as a yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:31]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2ccccc21
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2)c2ccccc21
Yield: 70 %

Procedure:
According to the procedure described in example 3, step E; [3-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (94 mg, 0.22 mmol) in DMF (3.5 mL) was alkylated with benzyl bromide to give, after work-up and chromatography, [3-(3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (80 mg, 70% yield). 1H-NMR (CDCl3): δ 8.38 (m, 1H), 7.52 (m, 1H), 7.42 (m, 1H), 7.22–7.37 (m, 9H), 7.12 (m, 1H), 5.97 (m, 1H), 5.82 (m, 1H), 5.09 (s, 2H), 3.78 (s, 3H), 3.68 (m, 1H), 2.94 (m, 1H), 2.08 (m, 1H), 1.93 (m, 1H), 1.81 (m, 2H), 1.73 (m, 1H), 1.62 (m, 2H), 1.35 (m, 2H). MS: calculated for C33H31N5O3+H 521.3; found: 521.2.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23](O)=[O:24])[CH:13]=2)[CH2:3][CH2:2]1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:23]([C:14]2[CH:13]=[C:12]([O:11][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:1][CH2:2][CH2:3]3)[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=2)=[O:24])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Product: CC(=O)N1CCN(C(=O)c2cc(OC3CCOc4ccccc43)c3nc(C)n(C)c3c2)CC1
Yield: 38 %

Procedure:
The title compound was prepared as a white solid in 38% yield (35 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2 in Example 11) and 1-acetylpiperazine (53 mg, 0.42 mmol) by the same manner in STEP 3 in Example 11: 1H NMR (CDCl3) δ: 7.31-7.23 (m, 2H), 7.21 (s, 1H), 6.89-6.77 (m, 3H), 6.50-6.00 (m, 1H), 4.50-4.40 (m, 1H), 4.27-4.32 (m, 1H), 3.75 (s, 3H), 3.80-3.36 (m, 8H), 2.64 (s, 3H), 2.40-2.19 (m, 2H), 2.13 (s, 3H) ppm;
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>CO.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(OCCCNc2ccc3c(c2)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCCCNc2ccc3c(c2)OCO3)cc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 68.9 %

Procedure:
Methyl 4-[3-[N-(3,4-methylenedioxyphenyl)amino]propoxy]benzoate (1.5 g) was suspended in methanol (20 ml), and thereto a solution of sodium hydroxide (0.55 g) in water (5 ml) was added, then, the mixture was heated with stirring at 60° C. for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was washed with ether several times, and further thereto were added water and a neutralization amount of conc. hydrochloric acid. The resulting crystal was collected by filtration to give the desired product (0.99 g). mp. 164°-167° C. (decomposed).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[S:5][CH:6]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[S:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Reactant: OB(O)c1ccncc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccncc2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from (R)-3′-(4-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-4-boronic acid. The solid obtained after flash chromatography was further purified by reverse phase HPLC on a Phenomenex® Polar RP column using a gradient of 5-45% acetonitrile/water (each solvent containing 0.1% trifluoroacetic acid as a buffer) as the eluant. The residue was partitioned between saturated aqueous potassium carbonate and chloroform and the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound as a pale solid (74 mg), m/z 342 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O)C.Cl>[Fe].O>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(I)cnc1N
Temperature: 100 °C
Yield: 59.8 %

Procedure:
5-Iodo-3-nitro-2-aminopyridine (2.0 g, 7.55 mmol), ethanol (7 mL), water (2 mL), and concentrated HCl (0.10 mL) were added to a 25 mL round bottom flask and allowed to stir. Iron (4.8 g, 85.9 mmol) was added in portions to the reaction followed by heating at 100° C. for 30 min. The iron was then removed and washed with ethanol over a flitted filter while the ethanol washings were concentrated under reduced pressure. The residue was purified by flash chromatography using 1:2 hexane:ethyl acetate as eluent to give 5-Iodo-2,3-diaminopyridine as a light brown solid (60%, 1.061 g).