Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[SH2:14].C(NCC)C>CN(C=O)C>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[S:14])=[CH:8][N:7]=1
Reactant: S
Reactant: N#Cc1ccc(OCCCO)nc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: NC(=S)c1ccc(OCCCO)nc1
Temperature: 60 °C

Procedure:
Through a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 66, 16 g, 89.79 mmol) in DMF (450 mL) was passed H2S for 3 h at rt. The reaction mixture turned purple. Diethylamine (9.85 g, 134.69 mmol) was added slowly. The resultant dark green solution was heated at 60° C. for 2 h. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography with a gradient of EtOAc in hexanes from 50 to 100%. The title compound was collected as a yellow solid (18.9 g, 98%). 1H NMR (400 MHz, acetone-d6) δ 8.98-8.87 (br, 2H), 8.80-8.79 (m, 1H), 8.29 (dd, 1H), 6.77 (dd, 1H), 4.48 (t, 2H), 3.74-3.68 (m, 3H), 1.99 (t, 2H). LC/MS m/z 213.2 (M+H)+; RT 0.50 min.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:35]=[C:36]([NH:39]C=O)[S:37][CH:38]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[NH2:39][C:36]1[S:37][CH:38]=[C:34]([C:11](=[N:10][O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:12]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:35]=1
Reactant: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A mixture of tert-butyl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (2.6 g) and conc. hydrochloric acid (0.9 g) in methanol (20 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was added to ethyl acetate and water, and then adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated organic layer was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave tert-butyl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (2.17 g).
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[C:19]([OH:24])(=[O:23])[C@H:20]([CH3:22])[OH:21].C[C@H]1OC(=O)[C@@H](C)OC1=O.[CH3:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[C:3]([OH:5])(=[O:4])[C@H:2]([CH3:1])[OH:9].[CH3:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42].[C:19]([OH:24])(=[O:23])[C@@H:20]([CH3:22])[OH:21]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: CCCCC(CC)C(=O)[O-]
Agent: C[C@H](O)C(=O)O
Agent: C[C@H]1OC(=O)[C@@H](C)OC1=O
Solvent: COCCOCCO
Product: C[C@@H](O)C(=O)O
Reaction time: 4 h

Procedure:
Ringopening polymerization of lactide (L-lactide for system (A) and D-lactide for system B, each 5 g) was carried out using 2-(2-methoxyethoxy)ethanol (MEE, 0.556 g) as an initiator, and stannous octoate (0.093 g) as the catalyst. The polymerization was carried out in the melt at 130° C. for four hours to yield MEE-L-lactic acid oligomer (A) and MEE-D-lactic acid oligomer (B). FIG. 1 shows the reaction scheme for the synthesis of dex-lactate (8), in which the DP is the degree of polymerization and DS is the degree of substitution (number of lactic acid oligomers per 100 glucopyranose units of dextran.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C:11]([CH3:28])([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:43]1([N:46]2[CH:51]=[CH:50][C:49](I)=[CH:48][C:47]2=[O:53])[CH2:45][CH2:44]1>COCCOC.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:43]1([N:46]2[CH:51]=[CH:50][C:49]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:7]4[CH2:6][CH2:5][C:4]([CH2:3][C:2]([OH:1])([CH3:36])[CH3:35])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:9][C:8]4=[O:10])([CH3:12])[CH3:28])=[CH:18][CH:17]=3)=[CH:48][C:47]2=[O:53])[CH2:45][CH2:44]1
Reactant: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: O=c1cc(I)ccn1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(-c3ccn(C4CC4)c(=O)c3)cc2)C(=O)O1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 112.2 %

Procedure:
To a solution of 6-(2-Hydroxy-2-methyl-propyl)-3-{1-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one (50 mg, 151.5 μmol) in DME (10 mL) were added a solution of sodium carbonate (64.5 mg, 609 μmol) in EtOH (2 mL) and water (1 mL), 1-cyclopropyl-4-iodo-1H-pyridin-2-one (19 mg, 73 μmol) and Pd(PPh3)4(7.5 mg, 6 μmol) successively under nitrogen. The reaction mixture was stirred at 100° C. for 2.5 h and then concentrated under vacuum. The residue was dissolved in water, extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by preparative prep HPLC to afford 3-{1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-methyl-ethyl}-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (41 mg, 71%). 1H NMR (CDCl3) δ 7.45-7.25 (m, 8H), 7.12-7.10 (d, 2H), 6.75 (s, 1H), 6.40 (d, 1H), 3.39-3.29 (m, 2H), 2.90-2.83 (m, 1H), 2.39-2.21 (m, 4H), 1.67 (d, 3H), 1.50 (s, 3H), 1.16-1.12 (m, 5H), 1.02 (s, 3H), 0.92-0.87 (m, 2H); LC-MS Method 2 tR=1.10 min, m/z=501.
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:33])=O>>[Cl:33][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Product: CCOC(=O)C(Cl)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 63 %

Procedure:
A mixture of ethyl 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (320 mg) and thionyl chloride (3 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:4, v/v) gave ethyl 2-chloro-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (210 mg, 63%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[C:5]([F:17])=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]1.[C:27](N1C=CN=C1)([N:29]1C=CN=C1)=O.CN>>[CH3:27][NH:29][C:24]([CH:20]1[CH2:21][C:22](=[O:23])[N:18]([C:3]2[CH:4]=[C:5]([F:17])[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[CH:7][C:2]=2[F:1])[CH2:19]1)=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CC(=O)N(c2cc(F)c(OCc3cccc(F)c3)cc2F)C1
Agent: CN
Product: CNC(=O)C1CC(=O)N(c2cc(F)c(OCc3cccc(F)c3)cc2F)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of 365 mg (1.0 mmol) of (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid is treated with 178 mg (1.1 mmol) of 1,1′-carbonyl-diimidazole, and the mixture is heated at 50° C. for 2 hours. Thereafter, the solution is cooled to RT and 47 mg (1.5 mmol) of methylamine (33% solution in ethanol) are added. After 18 hours the reaction is not complete, so that another 47 mg (1.5 mmol) of methylamine (33% solution in ethanol) are added and stirring is continued for 24 hours at 50° C. For the working-up, the reaction mixture is evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 95:5-mixture of dichloromethane and methanol as the eluent. There are obtained, after crystallization from ether, 136 mg (36% of theory) of the (RS)-1-[2,5-difluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as an off-white solid. MS: m/e=379 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccccc1O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A flask with a stirrer was charged with 5.46 g of 2-aminophenol, 5.05 g of triethylamine and 100 ml of tetrahydrofuran, and a solution of 10.55 g of 4-chlorobenzenesulfonyl chloride in 20 ml of tetrahydrofuran was dropwise added with cooling with ice over 10 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethanol/n-hexane mixed solvents, to give 8.9 g of an end product. Melting point 82° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)[C:27]1=[O:58]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH3:25][N:26]1[C:27](=[O:58])[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:55][O:56][CH2:57]4)[CH2:50][CH2:49]3)=[CH:44][N:43]=2)=[CH:29][C:30]([C:2]2[C:3]([CH:23]=[O:24])=[C:4]([N:8]3[CH2:19][CH2:18][C:17]4[C:16]5[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=5[S:11][C:10]=4[C:9]3=[O:22])[N:5]=[CH:6][CH:7]=2)=[CH:31]1
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 109a (75 mg, 0.2 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (94 mg, 0.2 mmol), Pd(dppf)Cl2 (17 mg, 0.02 mmol), K3PO4.3H2O (140 mg, 0.6 mmol), and tetrahydrofuran (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to 109b as yellow solid (60 mg, 47%). MS: [M+H]+ 666.
Reaction SMILES: C(OC([CH:8]1[C:12]2[N:13]=[C:14]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH3:27])[CH2:20][CH2:19]3)[N:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:28])=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:27][O:26][CH2:25][CH2:24][N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]3[NH:10][C:9](=[O:28])[CH2:8][C:12]=3[N:13]=2)[CH2:23][CH2:22]1
Reactant: COCCN1CCC(Nc2ncc3c(n2)C(C(=O)OC(C)(C)C)C(=O)N3)CC1
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCC(Nc2ncc3c(n2)CC(=O)N3)CC1
Yield: 100 %

Procedure:
Crude 2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-6-oxo-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid tert-butyl ester, acetate salts (7, 785 mgs, ˜1.5 mmol) was stirred in neat TFA for 30 min at room temperature. The reaction mixture was concentrated in vacuo. The resulting residue was suspended in toluene and reconcentrated in vacuo to remove residual TFA, then dried under high vacuum for several hours to give 2-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-5,7-dihydro-pyrrolo[3,2-d]pyrimidin-6-one (8, 1.1 g, ˜1.5 mmol) as a mixture of TFA salts which was used in the next reaction without further purification. LC/MS Calcd for [M+H]+ 292, found 292.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:24][S:25]([CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)(=[O:27])=[O:26]>>[CH:19]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][N:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cnn(CS(C)(=O)=O)c2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CS(C)(=O)=O)c3)ccc1-2

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 was reacted with 1-Methanesulfonylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 430. MS (ESI+) 471.1. 1H NMR (400 MHz, DMSO) δ 8.36 (m, 2H), 8.19 (s, 1H), 8.10 (s, 1H), 7.49 (dd, J=8.3, 1.8, 1H), 7.36 (d, J=1.7, 1H), 5.84 (m, 1H), 5.75 (s, 2H), 4.40 (t, J=5.0, 2H), 3.46 (t, J=5.0, 2H), 3.06 (s, 3H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>ClCCl>[CH2:1]([N:8]=[C:16]1[CH2:17][CH2:18][C:13]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: ClCCl
Product: c1ccc(CN=C2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4 Å molecular sieve (20 g) and benzylamine (8.90 g, 83 mmol) were added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (10.0 g, 64 mmol) in dichloromethane (100 ml), and the reaction mixture was stirred for 16 h at room temperature. The suspension was then filtered and the filtrate was concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.O(CC)[C:10]([S-:12])=[S:11].[K+].CN1CCCC1=O.C(O)(=O)C>O>[S:12]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][N:6]=2)[NH:1][C:10]1=[S:11]
Reactant: Nc1nccnc1Cl
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: S=c1[nH]c2nccnc2s1
Temperature: 150 °C
Yield: 66.7 %

Procedure:
To a mixture of 2-amino-3-chloropyrazine (5.0 g, 38.6 mmol) and potassium ethyl xanthate (9.28 g, 57.9 mmol) was added 1-methyl-2-pyrrolidinone (68 mL). The solution was stirred and heated at 150° C. for 16 h. After cooling to rt, glacial acetic acid (10 mL) and water (1500 mL) were added to the solution. The solid precipitate was filtered. The solid was suspended in 1:1 EtOH/water (500 mL) and sonicated. The solid was once again filtered, washed with water, and dried with CaSO4 in vacuo for 16 h to yield the product (4.36 g, 67%). 1H NMR (500 MHz, DMSO-d6): 14.69 (br s, 1H), 8.42 (d, J=2.8, 1H), 8.39 (d, J=2.8, 1H). MS (ESI): mass calcd. for C5H3N3S2, 168.98; m/z found, 170.00 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(O[N:34]1N=NC2C=[CH:38][CH:39]=[CH:40][C:35]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CCCC1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([CH:14]([NH:13][C:11](=[O:12])[C:9]3[CH:8]=[CH:7][C:3]([C:4]([N:34]4[CH2:35][CH2:40][CH2:39][CH2:38]4)=[O:6])=[C:2]([Cl:1])[CH:10]=3)[CH3:15])=[N:17][C:18]=2[CH:24]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 56 %

Procedure:
Prepared analogously to Example 1g from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and pyrrolidine in tetrahydrofuran. Yield: 56%; Rf value: 0.49 (silica gel; dichloromethane/ethanol=9:1); C21H20Cl2N4O2 (431.32); mass spectrum: (M+H)+=433/433/435 (chlorine isotope).
Reaction SMILES: C([O-])(=O)C.[K+].[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[C:21]([O:29][CH2:30][O:31][CH3:32])[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13](Cl)[N:14]=1)[CH2:7][CH2:8][CH3:9]>[Pd].CO>[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[C:21]([O:29][CH2:30][O:31][CH3:32])[CH:20]=2)[C:12]([CH:16]=[O:17])=[CH:13][N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(=O)OC)c(OCOC)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)c(OCOC)c1
Reaction time: 0.67 h
Yield: 86.8 %

Procedure:
To a suspension of 0.32 g of 10% palladium on carbon in 15 mL of methanol containing potassium acetate (0.813 g, 8.28 mmol) was added a solution of 2-n-butyl-1-(4-carbomethoxy-3-methoxymethoxyphenyl)methyl-4-chloro-1H-imidazol-5-carboxaldehyde (3.27 g, 8.28 mmol) in 60 mL of methanol. The reaction was hydrogenated at 4 psi for 40 minutes. The solid was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether and water. The pH of the aqueous layer was adjusted to 7.5 with 5% sodium carbonate solution. The layers were separated and the organic layer was washed with brine and dried with magnesium sulfate. The solvent was removed in vacuo to give 2.59 g (87%) of product as an oil.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21]>>[CH3:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[O:21][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C[C@@H]1CCC[C@H]1O
Product: C[C@@H]1CCC[C@H]1Oc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 158c from 2,6 dinitrobenzonitrile and trans-2-methylcyclopentanol in 65% as a yellow solid. MS 247 (MH+).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[NH:4].[CH2:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][N:18]=1)[CH2:15][CH3:16].C(Cl)CCl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.C1COCC1.CCOC(C)=O>[NH:9]1[C:10]2[C:6](=[C:5]([C:3]3[N:4]=[C:21]([C:20]4[CH:19]=[N:18][C:17]([CH2:14][CH2:15][CH3:16])=[CH:25][CH:24]=4)[O:1][N:2]=3)[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: N=C(NO)c1cccc2[nH]ccc12
Reactant: CCCc1ccc(C(=O)O)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A mixture of the product of Example 34, Step A (0.087 g; 0.5 mmol), 6-propylnicotinic acid (0.082 g; 0.5 mmol) and EDC (0.11 g; 0.57 mmol) in anhydrous DMSO (2 ml) was stirred for 1 h at ˜40° C. under N2. To this 1M TBAF in THF (0.5 ml) was added and the resulting mixture was stirred for 1 h at ˜110° C. After cooling to room temperature the mixture was diluted to 15 ml with EtOAc, washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness. The residue was purified by FCC (SiO2, CH2Cl2:EtOAc 9:1) to give the title compound (0.05 g; 33%), as colorless solid. 1H-NMR (CDCl3) 1.0 (m, 3H); 1.8 (m, 2H); 2.88 (tr, 2H, J=9 Hz); 7.3-7.4 (m, 4H); 7.57 (d, 1H, J=9 Hz); 8.08 (dd, 1H, J=2, 9 Hz); 8.38-8.43 (m, 2H); 9.39 (d, 1H, J=2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:11])[CH3:10])=[C:4]([Cl:12])[N:3]=1>ClCCCl.O=[Mn]=O>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: CC(O)c1c(Cl)nc(N)nc1Cl
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: CC(=O)c1c(Cl)nc(N)nc1Cl
Yield: 69.8 %

Procedure:
1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanol (2.0 g, 9.6 mmol) was treated with MnO2 (20 g, 229 mmol, 24 equiv.) in 1,2-dichloroethane for 16 h at 70° C. Filtration over celite and concentration gave 1-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone as a pale orange solid (1.4 g, 6.7 mmol, 71%), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][C:34]2=[O:41].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[C:36](=[O:40])[NH:35][C:34]5=[O:41])=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc5c(c4)C(=O)NC5=O)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.2 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol) and 5-aminoisoindoline-1,3-dione (19 mg, 0.12 mmol) in pyridine (8 mL) was added POCl3 (0.3 mL, 3.23 mmol) at 0° C., the reaction mixture was stirred at room temperature for 4 hours, a sat. NaHCO3 solution was added slowly, the solvent was removed in vacuo, water (5 mL) and methanol (2 mL) were added. The precipitate was collected by filtration and washed with water (5 mL) and methanol (5 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide (27 mg, 40.0%) as an orange solid. 1H NMR (300 MHz, DMSO): δ 11.20 (s, 1H), 10.59 (s, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.13 (s, 1H), 7.86-7.73 (m, 2H), 7.63 (s, 1H), 7.38-7.29 (m, 1H), 6.78 (s, 1H), 4.77 (d, 1H, J=12.0 Hz), 4.62 (d, 1H, J=12.3 Hz), 3.66 (s, 3H), 3.61 (s, 3H), 3.16-2.94 (m, 2H), 2.60-2.55 (m, 1H), 2.04-2.01 (m, 1H), 1.76-1.72 (m, 2H), 1.52-1.41 (m, 1H). LC-MS: 560 [M+H]+, tR=1.49 min. HPLC: 99.49% at 214 nm, 99.47% at 254 nm, tR=5.33 min.