Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[OH:28])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(N(C)C)=O.C1OC1C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:27])[CH:19]([NH:20][C:21](=[S:26])[CH2:22][CH2:23][C:24]#[N:25])[C@H:16]3[S:15][CH2:14][C:13]=2[O:28][S:42]([CH3:41])(=[O:44])=[O:43])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: N#CCCC(=S)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CS(=O)(=O)Cl
Agent: CC1CO1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Reaction time: 4 h

Procedure:
To a solution of 2.5 g. of 7-cyanomethylthioacetamido-3-cephem-3ol-4-carboxylic acid p-nitrobenzyl ester in 25 ml. of dry dimethylacetamide is added 1 ml. of propylene oxide and one equivalent of methanesulfonyl chloride. After stirring for 4 hours, the mixture is taken up in ethyl acetate and washed with saturated sodium chloride solution. Solvent is removed from the ethyl acetate solution under reduced pressure and the residue is purified by thin layer chromatography yielding the product 7-cyanomethylthioacetamido-3-methylsulfonyloxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][CH:30]1[CH2:33][CH2:32][CH2:31]1.CN(C=O)C>O>[CH:30]1([CH2:29][O:1][C:2]2[C:3]3[N:4]([C:8]([C:12]([NH:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][OH:17])=[O:13])=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(O)cccn12
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCC3CCC3)cccn12
Reaction time: 1 h

Procedure:
100 mg (0.34 mmol) of 8-hydroxy-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide, 246 mg (0.76 mmol) of caesium carbonate and 56 mg (0.38 mmol) of (bromomethyl)cyclobutane were added to 4.9 ml of dry DMF and the mixture was stirred for 60 min in an oil bath preheated to 60° C. After cooling, about 40 ml of water were added to the reaction mixture and the solution formed was extracted 3× with ethyl acetate. The combined organic phases were concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: water/methanol gradient with addition of 0.1% TFA). All product-containing fractions were combined and concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, concentrated and dried under high vacuum. This gave 78 mg of the target compound (63% of theory, purity 100%).
Reaction SMILES: [Na].ClC(Cl)(Cl)[C:4]([C:6]1[NH:7][CH:8]=[C:9]([I:11])[CH:10]=1)=[O:5].[CH3:14][OH:15]>>[CH3:14][O:15][C:4]([C:6]1[NH:7][CH:8]=[C:9]([I:11])[CH:10]=1)=[O:5]
Reactant: CO
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Agent: [Na]
Product: COC(=O)c1cc(I)c[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 300 mL of dry methanol was added 0.52 gm (0.023 mol) of sodium and the solution was stirred until all sodium was reacted. The solution was cooled to 0° C. and 19.5 gm (0.057 mol) of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)-ethanone was added as a solid over a 15 min period. After 15 min at 0° C. the solution was warmed to room temperature and stirred for an additional 2 h. The solvents were removed at reduced pressure and the residue dissolved in diethyl ether. The ether layer was washed with H2O, saturated brine, dried (Na2SO4) and the solvents removed at reduced pressure. The solid was recystallized from hot hexanes-trace EtOAc to yield 13.7 gm (95% yield) of a light brown solid. This was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])[C:19]([Cl:31])=[CH:18][N:17]=1.Cl.[Na]>O.CC(O)C>[Cl:31][C:19]1[C:20]([NH:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NC4CCCCNC4=O)n3)cc2CC1
Temperature: 120 °C
Yield: 26 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (75 mg 0.20 mmol), 3-(2,5-Dichloro-pyrimidin-4-ylamino)-azepan-2-one (57 mg, 0.30 mmol) and 81 μl of 4N HCl in dioxanes were combined into 1 ml IPA in a microwave tube. The reaction was heated to 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-20% methanol in methylene chloride as the eluent to yield 3-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-azepan-2-one (22.33 mg, 19%). MP: 232-234° C.; 1H-NMR (CDCl3) δ 7.99 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.16 (s, 1H), 7.08 (d, J=8 Hz, 1H), 6.97 (s, 1H), 6.83 (d, J=6 Hz, 1H), 6.30 (br s, 1H), 4.69 (q, J=9.9, 5.56 Hz, 1H), 3.32 (m, 2H), 2.92 (m, 4H), 2.72-2.52 (m, 6H), 2.25 (d, J=3.9 Hz, 1H), 2.05 (d, J=4.2 Hz, 1H), 1.95-1.65 (m, 2H), 1.60-1.40 (m, 2H), 1.08 (t, J=7 Hz, 3H); LC/MS (ESI+): 429 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([O:16][C:17]1[C:24]([O:25][CH2:26][CH3:27])=[C:23]([O:28][CH2:29][CH3:30])[CH:22]=[CH:21][C:18]=1[CH:19]=O)[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([O:25][CH2:26][CH3:27])[C:17]=2[O:16][CH2:14][CH3:15])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOc1ccc(C=O)c(OCC)c1OCC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(OCC)c1OCC
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 1.1 g (5.9 mmol) of N-Boc-piperazine and 1.40 g (5.9 mmol) of 2,3,4-triethoxybenzaldehyde are mixed in 25 ml of dry dichloromethane. After dissolution 2 drops of acetic acid is added, then 2.12 g (10 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 10 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off and concentrated in vacuum at 50÷80° C. The residue (2.2 g of yellowish oil) is used on the next step.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>O>[Cl:1][S:2]([C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:8]([O:7][CH3:6])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:5])=[O:3]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: COc1cc(S(=O)(=O)Cl)cc(C(=O)O)c1OC
Yield: 81.1 %

Procedure:
To a solution, cooled to -5° C., of 511.7 g (200 ml) of chlorosulfonic acid (ClSO3H) are slowly added 80 g of 2,3-dimethoxy benzoic acid. Then the temperature is allowed to rise to 15° C., the mixture is poured into a solution of water and ice, and the precipitate formed is filtered. Thus, 100 g (yield: 80%) of 5-chlorosulfonyl 2,3-dimethoxy benzoic acid are obtained [(IIb), Melting point: 157° C⟧
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8](=[O:15])[N:9]([CH3:14])[CH:10]=[C:11](Br)[CH:12]=2)=[N:2]1.[C:16]([O:19][CH2:20][C:21]1[C:22]([N:36]2[CH2:47][CH2:46][N:45]3[C:38](=[CH:39][C:40]4[CH2:41][C:42]([CH3:49])([CH3:48])[CH2:43][C:44]=43)[C:37]2=[O:50])=[N:23][CH:24]=[CH:25][C:26]=1B1OC(C)(C)C(C)(C)O1)(=[O:18])[CH3:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:36]2[CH2:47][CH2:46][N:45]3[C:38](=[CH:39][C:40]4[CH2:41][C:42]([CH3:49])([CH3:48])[CH2:43][C:44]=43)[C:37]2=[O:50])=[N:23][CH:24]=[CH:25][C:26]=1[C:11]1[CH:12]=[C:7]([NH:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[C:8](=[O:15])[N:9]([CH3:14])[CH:10]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc[nH]n2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 289b (200 mg, 0.74 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-{3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (360 mg, 0.90 mmol), PdCl2(dppf) (41 mg, 0.050 mmol), K3PO4 (320 mg, 1.5 mmol), sodium acetate (123 mg, 1.5 mmol), acetonitrile (10 mL), and water (0.2 mL). The system was evacuated and then refilled with N2. Then it was heated at 90° C. for 4 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 289c as a pale yellow solid (150 mg, 38%). MS-ESI: [M+H]+ 542.3.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][N:9]([CH:14]([CH3:16])[CH3:15])[S:10](=[O:13])(=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][Cl:22]>CN(C=O)C>[Cl:22][CH2:21][CH2:20][N:11]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=2[CH2:8][N:9]([CH:14]([CH3:16])[CH3:15])[S:10]1(=[O:13])=[O:12]
Reactant: CC(C)N1Cc2c(F)cccc2NS1(=O)=O
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1Cc2c(F)cccc2N(CCCl)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (0.22 g, 0.9 mmol) in dry DMF (15 ml) was added via cannula to a flask containing NaH (25 mg, 0.99 mmol) and DMF (7 ml) in argon atmosphere, and stirred for 2 hours at room temperature. 1-Bromo-2-chloroethane (0.19 ml, 2.25 mmol,) was then added dropwise and the mixture stirred at room temperature for 4 days. Then, the mixture was extracted with EtOAc (3×50 ml). The combined organic extracts were washed with water (1×100 ml) and then brine (1×100 ml), dried over Na2SO4 and solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:Hexane 1:4) affording pure 1-(2-chloroethyl)-5-fluoro-3-(1-methylethyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [C:1](O)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[N:13]1([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[O:11])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Product: NC(=O)c1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1
Yield: 50 %

Procedure:
The title compound is prepared from terephthalamic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 50% of theory; LC (method 1): tR=3.07 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [C:1](=[O:22])(OCCCCCCCCCCCCCCCCCC)[NH2:2].CC(O)C.[NH2:27][CH2:28][CH2:29][CH:30]([NH2:33])[CH2:31][CH3:32].O=C=[N:36]C1CC(C)(C)CC(C)(CN=C=O)C1>CCCCCCC.C1(C)C(C)=CC=CC=1>[NH2:27][CH2:28][CH2:29][CH:30]([NH2:33])[CH2:31][CH3:32].[NH2:36][C:1]([NH2:2])=[O:22]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CCCCCCCCCCCCCCCCCCOC(N)=O
Agent: CCC(N)CCN
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Solvent: CC(C)O
Product: NC(N)=O

Procedure:
To a solution of 4.4 grams of polyoctadecyl carbamate-co-vinyl acetate having 50 mole % octadecyl carbamate (prepared in xylene at 40 percent solids as described above) and 1.58 grams of polyvinyl butyral (available under the trade designation "BUTVAR" B72 from Monsanto Company, St. Louis, Mo.) in a solvent mixture of 178.6 grams of 2-propanol, 20.6 grams of xylene and 59.9 grams of heptane was added 0.40 grams of 5,000 Mn polydimethylsiloxane diamine (PDMS, prepared following U.S. Pat. No. 5,512,650) and 0.50 grams of 1,3-diaminopentane (available under the trade designation "DYTEK" EP from DuPont) with stirring at 25° C. Next, 1.10 grams of isophorone diisocyanate (IPDI available from Huls or Bayer) was added at 25° C. with stirring and a slow nitrogen purge. The mixture was stirred for 30 minutes, and, in the presence of the polyoctadecyl carbamate-co-vinyl acetate and the polyvinyl butyral, the IPDI reacted with the PDMS diamine and the 1,3-diaminopentane to form a polydiorganosiloxane urea-containing component with 20 weight % PDMS and 80 weight % 1,3-diaminopentane/IPDI. The final product mixture was a homogeneous, hazy, approximately 3% solids solution of a polymer component (polyoctadecyl carbamate-co-vinyl acetate), a polydiorganosiloxane urea-containing component and polyvinyl butyral in a 55:25:20 solids weight ratio.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[NH:15][C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:13]2.Br[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32]>>[Cl:32][CH2:31][CH2:30][CH2:29][CH2:28][N:11]1[C:10]([O:9][CH3:8])=[N:18][C:17]2[C:12]1=[N:13][C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:15][C:16]=2[NH2:19]
Reactant: ClCCCCBr
Reactant: CCCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([CH3:37])[C:33]2[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26][C:25]1=[O:36]>>[CH3:35][O:34][C:30]1[CH:31]=[CH:32][C:33]2[C:24]3([CH3:37])[C:25](=[O:36])[CH:26]([CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:27][C:28]=2[CH:29]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2(C)CCCCCl
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Product: COc1ccc2c(c1)CC1CCCCC2(C)C1=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one, there is obtained from 30.5 g. of 1-(4-chlorobutyl)-1-methyl-6-methoxy-2-tetralone 15 g. of the title product, b. p. 140° to 145° C. (0.5 mm.).
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][C@H:60]([OH:63])[C@@H:59]([CH3:64])[CH2:58]2)[CH3:56])CC1>>[ClH:43].[ClH:1].[OH:63][C@H:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:56])[CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:58][C@@H:59]1[CH3:64]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5coc6ccc(Cl)cc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 56 analogously to the method described in example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5].[Br:18][CH2:19][C:20](Br)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1

Procedure:
A solution of 41 g (0.165 mole) 2-amino-5-chloro-4'-hydroxybenzophenone in 800 ml of ether and 200 ml of water was cooled to 5°. The mixture was stirred while 20 ml (0.277 mole) of bromoacetyl bromide and a 20% solution of sodium carbonate were added alternately keeping the solution slightly basic. After 20 min. the reaction mixture was filtered to collect 60 g (about 100%) of product mp 201°-202°. Recrystallization from ethanol gave colorless prisms, mp 201°-203°.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:9]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][C:12]=3[N:11]([C:18]([NH:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23])=[O:19])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=CC(C(Cl)=O)=CC=1.FC1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F>>[CH3:27][C:26]([CH3:29])([CH3:28])[C@H:21]([NH:20][C:18]([N:11]1[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[CH:2][CH:3]=2)=[N:10]1)=[O:19])[C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCNC2)C(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Agent: O=C(Cl)c1ccc(F)cc1
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)cc2)c2c1CCNC2)C(C)(C)C

Procedure:
Compound 53 was prepared according to the procedure described for the synthesis of compound 52 by replacing 3,4-difluorobenzoyl chloride with 4-fluorobenzoyl chloride in the synthesis of intermediate 15. 1H NMR (CDCl3) δ 7.96 (d, J=9.5 Hz, 1H), 7.65-7.69 (m, 2H), 7.10-7.15 (m, 2H), 6.27 (br, 1H), 4.18 (d, J=9.4 Hz, 1H), 4.02 (s, 2H), 3.05-3.15 (m, 4H), 2.85 (d, J=4.8 Hz, 3H), 1.10 (s, 9H). LCMS (+ESI) m/z=388.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:15])[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:2]1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[CH:20]=[C:19]([CH3:29])[N:18]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:12][C:10]([F:13])([F:11])[C@@H:9]([O:8][C:7](=[O:15])[NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:17]2[N:18]=[C:19]([CH3:29])[CH:20]=[C:21]([NH:23][C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)[N:22]=2)[CH2:2]1)[CH3:14]
Reactant: Cc1cc(Nc2cc[nH]n2)nc(Cl)n1
Reactant: C[C@H](OC(=O)N[C@H]1CCNC1)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc[nH]n2)nc(N2CC[C@H](NC(=O)O[C@@H](C)C(F)(F)F)C2)n1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of (2S)-1,1,1-trifluoropropan-2-yl (3S)-pyrrolidin-3-ylcarbamate (50 mg) in DMSO (5 ml) was added 2-chloro-6-methyl-N-(1H-pyrazol-3-yl)pyrimidin-4-amine (46 mg) prepared in Referential Example 1 and DIEA (28 mg) at room temperature. The resulting mixture was stirred at 110° C. for 15 hours and then cooled to room temperature. The mixture was purified with preparative RP-HPLC to give (2S)-1,1,1-trifluoropropan-2-yl{(3S)-1-[4-methyl-6-(1H-pyrazol-3-ylamino)pyrimidin-2-yl]pyrrolidin-3-yl}carbamate as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:41]([Cl:42])=[CH:40][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:43])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd+2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:42][C:41]1[C:24]([NH:23][C:2]2[N:3]=[CH:4][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[C:8]4([CH2:19][CH2:20]4)[CH2:9][N:10]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:11]=3[N:12]=2)=[CH:25][C:26]([F:43])=[C:27]([CH:40]=1)[C:28]([NH:30][CH:31]1[CH2:32][CH2:33][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]1)=[O:29]
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN(C)C1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Agent: [Pd+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCC(N(C)C)CC4)cc3Cl)ncc21
Temperature: 100 °C
Yield: 28.2 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 103 mg, 0.32 mmol), 4-amino-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide (Intermediate 175; 92 mg, 0.29 mmol), and XANTPHOS (16 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium 10 carbonate (210 mg, 0.59 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (17 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (×3) and then heated at 100° C. for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, and the column then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (49 mg, 28%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1>CO.CC(C)=O.CC(O)=O>[CH3:1][N:2]([CH3:3])[CH2:25][C:23]1[N:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][C:16]=2[N+:27]([O-:29])=[O:28])[S:21][CH:22]=1
Reactant: Cc1ccc(-c2nc(C=O)cs2)c([N+](=O)[O-])c1
Reactant: CNC
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Cc1ccc(-c2nc(CN(C)C)cs2)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Dimethylamine (640 uL of a 2M solution in MeOH), sodium acetate, and sodium cyanoborohydride (56 mgs, 0.89 mmol) were stirred in 2.6 mL MeOH at room temperature under N2. Glacial HOAc was added to adjust the pH to 7-8. 2-(4-Methyl-2-nitro-phenyl)thiazole-4-carbaldehyde (159 mgs, 0.64 mmol) then was added as a solution in 3.2 mL of MeOH. After 2 h, product formation was apparent by mass spectroscopy. The reaction was allowed to proceed overnight. At that time, acetone (500 uL) was added to quench any unreacted borohydride and the reaction acidified to pH<3. The reaction was concentrated. The residue was partitioned between Et2O (30 mL) and H2O (30 mL). The aqueous phase was extracted with Et2O, then neutralized with 1N NaOH to pH 10. The aqueous phase was re-extracted with Et2O. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to provide the desired material.