Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:23]([CH3:45])([S:25][C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:24])[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][OH:71]>CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[OH:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][NH:65][C:20](=[O:22])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:23]([CH3:24])([S:25][C:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH3:45]
Reactant: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NCCCCCO
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a round bottom flask was added (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methyl-3-(tritylthio)butanoic acid (400 mg, 0.652 mmol), HOBT (120 mg, 0.782 mmol), Hunig's Base (0.137 mL, 0.782 mmol), DMF (1 mL) and DCM (5 mL). The reaction was stirred at rt for 1 hr. Then 5-aminopentan-1-ol (67.2 mg, 0.652 mmol) was added to the reaction and the reaction was stirred at rt overnight. The reaction was diluted with EtOAc (50 mL) and washed with water (4×15 mL) and saturated aqueous NaCl (15 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (R)-(9H-fluoren-9-yl)methyl 1-(5-hydroxypentylamino)-3-methyl-1-oxo-3-(tritylthio)butan-2-ylcarbamate (300 mg, 0.429 mmol, 65.9% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (d, J=7.70 Hz, 2H), 7.69-7.50 (m, 8H), 7.39 (t, J=7.42 Hz, 2H), 7.33-7.15 (m, 11H), 5.74-5.41 (m, 2H), 4.45-4.11 (m, 3H), 3.67-3.39 (m, 2H), 3.35-3.07 (m, 2H), 1.56-1.41 (m, 4H), 1.42-1.31 (m, 2H), 1.33-1.24 (m, 2H), 1.18 (br. s., 3H), 1.11 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 144.86, 141.28, 129.96, 127.86, 127.69, 127.07, 126.76, 125.11, 119.95, 68.35, 62.48, 53.38, 47.11, 39.35, 32.11, 29.01, 26.43, 22.93, 22.69, 14.09.
Reaction SMILES: C(OC([N:8]1[CH:12]([CH2:13][N:14]2[C:18]([C:19](OCC)=[O:20])=[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]([I:29])=[N:15]2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[OH:10][CH2:11][CH:12]1[CH2:13][N:14]2[N:15]=[C:16]([I:29])[C:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]2[C:19](=[O:20])[NH:8]1
Reactant: CCOC(=O)c1c(I)nn(CC2COC(C)(C)N2C(=O)OC(C)(C)C)c1C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(I)nn2c1C(=O)NC(CO)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
To a solution of Intermediate 351A (3.3 g, 5.99 mmol) in dioxane (10 mL) was added 4 M HCl in dioxane (5 mL, 5.99 mmol) and the resulting reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated and the crude product was basified with a 10% aqueous solution of sodium bicarbonate and extracted with EtOAc (3×100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated slowly (2 to 3 h) using a rotary evaporator at 60° C. to obtain Intermediate 351B (1.6 g, 67.4%) as a white solid. MS(ES): m/z=366 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J=3.0 Hz, 1H), 5.14 (t, J=5.5 Hz, 1H), 4.46-4.41 (m, 1H), 4.37-4.30 (m, 1H), 4.25 (q, J=7.0 Hz, 2H), 3.84-3.75 (m, 1H), 3.54-3.47 (m, 1H), 3.36 (s, 1H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[C:4](=[O:19])[NH:3]1.[H-].[Na+].Cl[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27](C(OC(C)(C)C)=O)[CH:26]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=2)[C:4](=[O:19])[N:3]1[CH2:24][C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1
Reactant: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the 4,4-dimethyl-1-{4-[(trifluoromethyl) sulfanyl]phenyl}tetrahydropyrimidin-2(1H)-one (10 mg, 0.03 mmol) in 2 mL DMF was added NaH (2.4 mg, 0.03 mmol). The mixture was allowed to stir at ambient temperature for 10 min. The reaction was treated with tert-butyl 3-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (8.8 mg, 0.03 mmol) and allowed to stir at ambient temperature for 16 h. The reaction was partitioned between water and ether. The organics were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 4,4-dimethyl-3-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-{4-[(trifluoromethyl)sulfanyl]phenyl}tetrahydropyrimidin-2(1H)-one. 1H NMR (399 MHz, CDCl3): δ 9.05 (s, 1 H); 8.30 (d, J=4.7 Hz, 1 H); 8.11 (d, J=7.9 Hz, 1 H); 7.63 (d, J=8.2 Hz, 2 H); 7.46-7.41 (m, 2 H); 7.36 (s, 1 H); 7.11-7.06 (m, 1 H); 4.80 (s, 2 H); 3.76-3.69 (m, 2H); 2.04-1.97 (m, 2 H); 1.36 (s, 6 H). LCMS [M+H]+=435.3.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4cccc(F)c4F)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (405 mg, compound B101), (2,3-difluorophenyl)boronic acid (118 mg), dichlorobis(tricyclohexylphosphine)palladium (28 mg) and aqueous cesium carbonate solution (0.563 ml, 2.0 M) in DME (10 ml) are reacted according to the procedure described in example B55 to afford the title compound after two times purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v) and amino phase silica gel elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v)] as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([Cu])#[N:13]>N1C=CC=CC=1.CCOC(C)=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1cnc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cnc2ccccc2c1
Temperature: 250 °C

Procedure:
A suspension of 3-bromoquinoline (1-Im-10, 1.5 g) and CuCN (3 eq) in 10 mL of pyridine in a 25 mL microwave tube was heated at 250° C. for 30 min in a microwave. This was repeated 10 times and the reactions were combined and diluted with 200 mL of EtOAc. The solids were removed by filtration and the EtOAc solution concentrated. The residue was taken up in a solution prepared from 80 mL of 30% aqueous NH3 and 800 mL of water. This was extracted with EtOAc (4×800 mL) then the combined extracts were dried with anhydrous Na2SO4, concentrated and purified by silica gel chromatography (PE:EtOAc=3:1) to give quinoline-3-carbonitrile (2-Im-10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:20][C:21]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:23][C:22]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:21]=4[Cl:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(O)cc1Cl
Temperature: 60 °C

Procedure:
The mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.36 mmol), 2-chloro-4-hydroxy-benzaldehyde (84.5 mg, 0.54 mmol), and piperidine (3 drops) in ethanol (3 mL) was heated at 60° C. oil bath for 4 hours, and cooled to room temperature. The product was crystallized out, filtered, washed by ethanol, and dried under high vacuum to provide pure 4-(3-chloro-4-fluoro-phenylamino)-5-[1-(2-chloro-4-hydroxy-phenyl)-methylidene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (br s, 1H), 10.45 (br s, 1H), 8.42 (s, 1H), 8.35 (br s, 1H), 7.65 (s, 1H), 7.11 (t, 1H), 6.96 (m, 1H), 6.79 (m, 1H), 6.72 (d, 1H), 6.66 (m, 1H), 6.56 (dd, 1H). MS 418 [M++1].
Reaction SMILES: C(OCC)(=O)C.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]=[N+]=[N-])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[OH:52][CH2:53][CH2:54][NH:55][C:56]([C@@H:58]1[CH2:62][CH2:61][CH2:60]N1)=[O:57]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]1[CH2:60][CH2:61][CH2:62][C@H:58]1[C:56]([NH:55][CH2:54][CH2:53][OH:52])=[O:57])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: O=C(NCCO)[C@@H]1CCCN1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO)OCc1ccccc1

Procedure:
To an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidinazide (4) prepared from Nα -benzyloxycarbonyl-L-histidine hydrazide (3) (6.07 g) by a known method was added 10 ml of a DMF solution of 2.31 g of (S)-N-(2-hydroxyethyl)-2-pyrrolidinecarboxamide (53) under ice-cooling and they were reacted overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (90:10:1), 3.43 g of Nα -benzyloxycarbonyl-L-histidyl-N-(2-hydroxyethyl)-L-prolinamide (54) was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([N:35]1[CH2:43][CH2:42][CH:38]([C:39]([OH:41])=O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCN(C(C)C)C(C)C.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([CH:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)=[CH:57][C:56]=1[C:67]1[N:68]=[C:69]([NH2:72])[S:70][CH:71]=1>C(#N)C>[CH:61]1([C:58]2[CH:59]=[CH:60][C:55]([O:54][CH3:53])=[C:56]([C:67]3[N:68]=[C:69]([NH:72][C:39]([CH:38]4[CH2:37][CH2:36][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:43][CH2:42]4)=[O:41])[S:70][CH:71]=3)[CH:57]=2)[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
1.68 g of BOP, 0.75 g of Boc-isonipecotic acid and then 1.41 mL of DIPEA are added, at a temperature of 0° C., to a solution of 1 g of 4-(2-methoxy-5-cyclohexylphenyl)-1,3-thiazol-2-amine, obtained in preparation I.3, in 6 mL of acetonitrile. The medium is stirred at room temperature for 24 hours and then filtered. The solid thus obtained is rinsed with acetonitrile and then dried. 1.13 g of a white solid are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:12](=[O:24])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:5][N:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C(=O)N([Br:42])C(=O)C1>C1COCC1>[Br:42][CH2:21][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)[O:13][C:12](=[O:24])[C:11]=1[C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(C)c(-c3cnc(OC)nc3OC)c(=O)oc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(CBr)c(-c3cnc(OC)nc3OC)c(=O)oc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(2,4-dimethoxy-pyrimidin-5-yl)-7-methoxy-4-methyl-chromen-2-one (210 mg, 0.64 mmoL) in anhydrous THF (5 mL) at −78° C. was added LiHMDS (1.0 M, 1.28 mmoL, 1.28 mL) dropwise. The resulting reddish solution was stirred at −78° C. for 20 min. To this solution was added NBS (114 mg, 0.64 mmoL) in THF (2 mL) slowly. The reaction was stirred for 2 hours at −78° C. and then quenched with sat. NaHCO3, warmed to room temperature. THF was removed in vacuo and the residue was partitioned between CH2Cl2 and water. The aqueous phase was extracted 3× with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford a yellow solid, which was then purified by silica gel column chromatography using hexanes:ethyl acetate (4:1 to 2:1) to afford the title product as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1C=C2N=NN(O)C2=CC=1.O.C(N=C=NC(C)C)(C)C.[CH:42]1[C:47]([S:48]([OH:51])(=[O:50])=[O:49])=[C:46]([OH:52])[C:45]([NH2:53])=[CH:44][C:43]=1[Cl:54]>CN(C=O)C.C(N(CC)CC)C>[Cl:54][C:43]1[CH:42]=[C:47]([S:48]([OH:51])(=[O:49])=[O:50])[C:46]([OH:52])=[C:45]([NH:53][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) and HOBt hydrate (65.6 mg, 0.43 mmol) were dissolved in 2 mL of DMF, and triethylamine (0.137 mL) was added thereto. After cooling the mixture down to 0° C., diisopropylcarbodiimide (66.4 μL, 0.43 mmol) and 2-amino-4-chlorophenol-6-sulfonic acid (73.7 mg, 0.33 mmol) were added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in 2 mL of TFA and stirred at room temperature for 2 hours. 2 mL of methylene chloride was added thereto, and a precipitate was taken by filtration to obtain a title compound.
Reaction SMILES: [CH2:1]([O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([NH:35][C@@H:36]([CH2:44][SH:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[CH:27]1[C:28]2[CH:29]([CH2:31][O:32][C:33]([NH:35][C@@H:36]([CH2:44][S:45][CH2:17][C@H:15]([OH:16])[CH2:14][O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[O:34])[C:30]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCCCCCCOC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCOC[C@@H](O)CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C

Procedure:
A solution of (S)-2-((dodecyloxy)methyl)oxirane (1.1 eq), (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 1 eq) and 1M K2CO3 (1.1 eq) in tBuOH (0.1 M) was stirred at 25° C. for 15 hours. The reaction mixture was concentrated en vaccuo to remove tBuOH and dissolved in EtOAc. The EtOAc solution was washed three times with water, and once with brine. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-30% EtOAc/Hex to give the title product as a colorless viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCC2CO2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
To a sealed tube was added 4-hydroxybenzamide (200 mg, 1.458 mmol), epichlorohydrin (135 mg, 1.458 mmol) and potassium carbonate (403 mg, 2.916 mmol) in 7 mL of dry DMF. The reaction mixture was stirred at 70° C. for 18 h. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 80 mg of 4-oxiranylmethoxy-benzamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21]OS(C)(=O)=O)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)CO.O1CCCC1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH:20]=[CH2:21])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: OCC(F)(F)F
Product: C=Cn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
4-(1-Vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester is the major product obtained from an alternative synthesis of 1-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (Preparation 44.2). Treat a stirred solution of 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (1.21 g, 2.77 mmol, Preparation 9), 2,2,2-trifluoroethanol (2.75 g, 27.4 numol, Aldrich Chemical Company), anhydrous tetrahydrofuran (20 mL) and dimethylformamide (2 mL) at 0-5° C. with sodium hydride (0.44 g, 11 mmol, 60% oil dispersion) under an argon atmosphere. Stir overnight at room temperature, heat at 50° C. for four hours, and stir at room temperature for two hours. Cool to 0° C., quench by addition of saturated ammonium chloride solution (5 mL) and concentrate in vacuo. Dissolve the residue in ethyl acetate (100 mL), wash with water (2×20 mL) and brine (20 mL), dry (Na2SO4) the organic phase, filter and concentrate to afford an oil. Purify the oil by flash chromatography (silica gel, 7×15 cm, ethyl acetate) to afford 0.97 g of 4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester as an oil, Rf=0.52 (silica gel, ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([N:27]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:22]2)[CH3:10])[C:5]([C:38]#[N:39])=[C:4]([CH3:40])[N:3]=1.O.NN>C(O)C.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([NH2:27])[CH2:22]2)[CH3:10])[C:5]([C:38]#[N:39])=[C:4]([CH3:40])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC[C@H](N3C(=O)c4ccccc4C3=O)C2)c1C#N
Agent: NN
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC[C@H](N)C2)c1C#N
Temperature: 65 °C
Yield: 46 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-(((S)-1-(6-((S)-3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile (20 mg, 0.037 mmol) and hydrazine monohydrate (0.081 mL, 1.7 mmol) in ethanol (1 mL). The mixture was heated to 65° C. for 4 hours. The mixture was diluted with acetonitrile and was then directly purified by preparative HPLC (basic mode, 25-45% ACN/water gradient). The product-containing fractions were combined and lyophilized to give the title compound as a light brown solid (6.9 mg, 46%). The absolute configuration of the stereocenter on the piperidine ring was not determined, but was assigned the opposite configuration of EXAMPLE 4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.56 (m, 3H), 1.84-1.96 (m, 1H), 2.01-2.12 (m, 2H), 2.14-2.26 (m, 2H), 2.31 (s, 4H), 2.57 (d, J=4.55 Hz, 2H), 2.89-2.99 (m, 1H), 3.43-3.51 (m, 1H), 3.59-3.67 (m, 1H), 3.78-3.85 (m, 3H), 6.27 (s, 1H), 6.53-6.56 (m, 1H), 7.43-7.47 (m, 1H), 7.88 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C21H27N9, 406. found 406.
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=2[CH3:21])=[C:11]2[C:6]([C:7]([C:22]([F:25])([F:24])[F:23])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:21])=[C:11]2[C:6]([C:7]([C:22]([F:25])([F:24])[F:23])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1C
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(O)cc1C
Yield: 80.1 %

Procedure:
Prepared according to Method D step C from 2-allyl-3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-2H-indazole (0.043 g, 0.124 mmol), boron tribromide (0.05 mL, 0.52 mmol) and 1.0 mL of cyclohexene to give the product (0.033 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH3:24])[N:18]=1)[CH:11]=[C:10]2[NH:25][CH:26]1[CH2:31][CH2:30]N[CH2:28][CH2:27]1>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14]([CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH3:24])[N:18]=3)[CH:11]=[C:10]2[NH:25][CH:26]2[CH2:27][CH2:28][N:3]([C:2](=[NH:4])[NH2:1])[CH2:30][CH2:31]2)=[CH:15][CH:16]=1
Reactant: N=C(N)N
Reactant: CNc1nccc(-c2cc(NC3CCNCC3)c3cc(OC)ccc3c2)n1
Product: CNc1nccc(-c2cc(NC3CCN(C(=N)N)CC3)c3cc(OC)ccc3c2)n1

Procedure:
4-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)piperidine-1-carboximidamide was synthesized according to General Procedure A: guanidine formation except 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 150 (0.018 g, 0.050 mmol) was used. The reaction mixture was triturated with ether (10 mL) to obtain 4-({7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}amino)piperidine-1-carboximidamide 204 as a solid (0.007 g). LC/MS (m/z): 406 [M+H].