Azzindani/Open_Reaction_Data huggingface dataset:
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]([CH2:30][C:31]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][N:55](COCC[Si](C)(C)C)[C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:34][N:33]([C:35]2[CH:36]=[CH:37][C:38]([C:41]([OH:43])=O)=[N:39][CH:40]=2)[CH2:32]1)#[N:29].Cl.[F:67][C:68]1([F:73])[CH2:71][CH:70]([NH2:72])[CH2:69]1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+].C(N)CN>C(Cl)Cl>[C:28]([CH2:30][C:31]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:32][N:33]([C:35]2[CH:36]=[CH:37][C:38]([C:41]([NH:72][CH:70]3[CH2:71][C:68]([F:73])([F:67])[CH2:69]3)=[O:43])=[N:39][CH:40]=2)[CH2:34]1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)nc5)C4)c3)ncnc21
Reactant: NC1CC(F)(F)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: NCCN
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(c2ccc(C(=O)NC3CC(F)(F)C3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (60.0 mg, 0.14 mmol), 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylic acid (48.4 mg, 0.0913 mmol), 3,3-difluorocyclobutanamine hydrochloride (20. mg, 0.14 mmol, Molbridge: Cat. #MB00001399) and N,N-diisopropylethylamine (64 μL, 0.36 mmol) in methylene chloride (2 mL) was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (2×2 mL). The combined organic layers were washed with water (1 mL), concentrated and dried under reduced pressure. The residue was dissolved in dichloromethylene (1 mL) and trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 1.5 hours, and concentrated under reduced pressure. The residue was dissolved in methanol (2.5 mL). Ethylenediamine (0.21 mL, 3.2 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=490.1. 1H NMR (300 MHz, DMSO-d6): δ 12.50 (br, 1H), 9.01 (s, 1H), 8.93 (d, J=7.8 Hz, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.70 (dd, J=3.4, 2.5 Hz, 1H), 7.15 (dd, J=3.5, 1.5 Hz, 1H), 7.04 (dd, J=8.6, 2.8 Hz, 1H), 4.63 (d, J=9.0 Hz, 2H), 4.36 (d, J=8.9 Hz, 2H), 4.23 (m, 1H), 3.73 (s, 2H), 2.80 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[C:5](=[O:22])[C:6]1[CH:7]=[CH:8][C:9]([C:20]#[N:21])=[CH:10][C:11]=1[C:12]2=[O:19].[N-:23]=[N+:24]=[N-:25].[Na+].Cl.C(N(CC)CC)C.Cl>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:4]=1[C:5](=[O:22])[C:6]1[CH:7]=[CH:8][C:9]([C:20]3[NH:25][N:24]=[N:23][N:21]=3)=[CH:10][C:11]=1[C:12]2=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(OC)c2c1C(=O)c1ccc(C#N)cc1C2=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c2c1C(=O)c1ccc(-c3nnn[nH]3)cc1C2=O
Temperature: 97 °C
Reaction time: 9 h

Procedure:
9,10-Dihydro-5,8-dimethoxy-9,10-dioxoanthracene-2-carbonitrile (1.005 g), sodium azide (0.334 g), triethylamine hydrochloride (0.708 g), dimethyl formamide (24 ml) and water (0.5 ml) were heated with stirring to 97° C. for 9 hours then cooled and poured into a mixture of water (210 ml) and 5N HCl (30 ml). The precipitate formed was isolated by filtration, washed with water and then dried in vacuo at 70° C. to give the tetrazole as a solid, m.p. 260°-262° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)[CH:5]=O.[C:13]([NH:17][C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[C:8]([NH2:10])[CH:7]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Product: CC(C)(C)NC(=O)C1CCN(Cc2cc(N)cc(Br)c2)CC1

Procedure:
The title compound is prepared according to the reactions described above starting from 3-bromo-5-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination BB-10a; LC-MS A: tR=0.65 min; [M+H]+=398.00 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.60 min; [M+H]+=369.67.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][N+:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9]>O>[Cl:2][CH2:3][N+:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9]
Reactant: COC(=O)CCC[N+](C)(C)CCl
Agent: [Cl-]
Solvent: O
Product: C[N+](C)(CCl)CCCC(=O)[O-]
Yield: 90.6 %

Procedure:
A solution of N-(chloromethyl)-4-methoxy-N,N-dimethyl-4-oxobutan-1-aminium chloride (5) (2.39 g, 10.38 mmol) in water (10 ml) was passed through Amberlite® IRA-410 (OH) ion exchange resin column (100 ml) slowly (ca. 0.5 ml/min) eluting with water. To the eluate Dowex® 50WX8 ion exchange resin by small portions was added until the pH of the medium of the initial 9.5 was decreased up to 6.8-7.0 (pH control by a pH-meter). The reaction mixture was filtered, evaporated, and the residue was azeotropically dried successively with acetone, isopropanol, and acetonitrile followed by drying in vacuo over P2O5 to give 1.69 g (91%) of 4-[(chloromethyl)(dimethyl)ammonio]butanoate. M.p. 100.5-101° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2ccccc2N)CC1
Yield: 77 %

Procedure:
4-(2-Nitro-phenylamino)-piperidine-1-carboxylic acid ethyl ester (from step 1 above) was dissolved in methanol then hydrogenated over 10% Pd/C (balloon pressure). The hydrogenation was run until the yellow color turned colorless. It was filtered through a celite pad, and the filtrated evaporated to a reddish brown residue. The residue was triturated with 1% ethyl acetate in hexanes and the solid collected by filtration to give 4-(2-amino-phenylamino)-piperidine-1-carboxylic acid ethyl ester (2.02 g; 77%, 2 steps). 1H NMR (CDCl3) δ 1.27 (t, 3H, J=7.2), 1.4 (m, 2H), 2.05 (m, 2H), 3.0 (m, 2H), 3.4 (m, 4H), 4.1 (m, 4H), 6.7 (m, 4H)
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([C:58]1[N:63]=[CH:62][C:61]([C:64](O)=[O:65])=[CH:60][CH:59]=1)#[N:57].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:64]([C:61]1[CH:60]=[CH:59][C:58]([C:56]#[N:57])=[N:63][CH:62]=1)=[O:65]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(C#N)nc1
Yield: 54.2 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), 6-cyano-3-pyridinecarboxylic acid (48.0 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was reduced in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to yield the title compound (77 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:19][CH2:20]1
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN1CCOCC1
Temperature: 0 °C
Yield: 17.2 %

Procedure:
A solution of Compound 107 (1 g, 2.64 mmol), 4-(2-chloro ethyl) morpholine (2.45 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient to yield 223 mg (17%) of white solids. M.P. 207° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 3.54 (m, 4H), 3.63 (m, 4H), 3.92 (m, 4H), 4.35 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.61 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 492 (M+1). Anal. (C26H29N5O3S) C,H, N.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C@H:14]([C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:25]1[CH2:26][OH:27])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.CS(C)=O>O>[O:1]([C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[C:11]([NH:13][C@H:14]([C:22]([N:24]1[CH2:30][CH2:29][CH2:28][C@H:25]1[CH:26]=[O:27])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CO)c1cccc(Oc2ccccc2)c1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 39.7 %

Procedure:
To 216.4 mg of N-(N-(3-phenoxybenzoyl)-L-phenylalanyl)-L-prolinol were added 0.92 ml of acetic anhydride-and 2.6 ml of DMSO. The mixture was stirred at room temperature for 22 hours. Then 40 ml of water was added to the reaction mixture. After stirring for an hour, the mixture was extracted 3 times with 20 ml each of dichloromethane. The oily layer was dried over anhydrous sodium sulfate and the solvent was distilled off to give 248.7 mg of an oily substance. The oily substance was purified by column chromatography (silica gel, developed with hexane-ethyl acetate) to give 85.5 mg of an amorphous solid. The solid was further purified by column chromatography (silica gel, developed with dichloromethane-ethyl acetate) to give 46.4 mg of the title compound as a colorless transparent amorphous solid. Yield, 21.5%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[CH3:17][C:18]1[S:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1.O>O1CCCC1.C(OCC)(=O)C>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:10]1[S:11][C:7]([CH:23]([C:21]2[S:22][C:18]([CH3:17])=[CH:19][CH:20]=2)[OH:24])=[CH:8][CH:9]=1
Reactant: Brc1ccc(C2OCCO2)s1
Reactant: Cc1ccc(C=O)s1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc(C3OCCO3)s2)s1
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
n-Butyl lithium (2.44N hexane solution, 7.4 mL, 17.9 mmol) was added dropwise to a solution of 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (4.0 g, 17 mmol) in tetrahydrofuran (50 mL) at from −75° C. to −70° C., and the solution was stirred for 10 minutes. 5-Methylthiophene-2-carbaldehyde (2.4 g, 18.7 mmol) was further added dropwise to the reaction solution at from −75° C. to −70° C. After dropwise addition was completed, the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction mixture, which was then partitioned, and the solvent was evaporated. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1, then 2:1), and the title compound (2.0 g, 7.09 mmol, 41.7%) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+].[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[CH:12]=[CH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1ncc2c(cc(Br)n2COCc2ccccc2)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C[Si](C)(C)CCOCn1ncc2c(ccn2COCc2ccccc2)c1=O
Yield: 195.7 %

Procedure:
To 5.00 g (10.8 mmol) of 1-benzyloxymethyl-2-bromo-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Reference example 33-(a) were added 50 ml of methanol, 30 ml of toluene, 1.5 g of potassium carbonate and 2.5 g of 51 palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 3 hours. After completion of the reaction, insoluble material of the reaction suspension was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 8.15 g of the title compound as a pale yellowish solid. (Yield: 77%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:18]([CH2:19][C:20]([O:22]CC)=[O:21])[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:26].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:18]([CH2:19][C:20]([O-:22])=[O:21])[C:17](=[O:25])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:26]
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CN1C(=O)C2(CCCC2)NC[C@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl [(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetate from Step C (90 mg, 0.26 mmol) in THF (3 mL) and H2O (1 mL) was added 1 N aqueous LiOH (0.31 mL, 0.31 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=325 (M+1).
Reaction SMILES: COC([N:5]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][C:7]=2[C:6]1=[O:16])=O.C[O-].[Na+]>O1CCOCC1>[Cl:15][C:10]1[CH:9]=[CH:8][C:7]2[C:6](=[O:16])[NH:5][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: COC(=O)N1CCc2nc(Cl)ccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1NCCc2nc(Cl)ccc21
Yield: 61.3 %

Procedure:
A mixture of 2-chloro-5-oxo-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.25 mmol) and sodium methoxide (40 mg, 0.75 mmol) in 2 mL of 1,4-dioxane was subject to microwave reaction at 110° C. for 30 min. After removal of 1,4-dioxane, the residue was dissolved in DCM and the DCM solution was washed with water and brine. The organic layer was then dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Prep-TLC separation (30% EtOAc in hexane) then afforded the tile compound (28 mg, 63%) as a white solid. MS: 183.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15])[CH3:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+:22]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:17])[CH:13]=[C:14]([NH2:22])[CH3:15])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@H](C)NC(=O)CC(C)=O)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc([C@H](C)NC(=O)C=C(C)N)cc1
Temperature: 100 °C

Procedure:
To a suspension of (S)—N-[1-(4-methoxy-phenyl)-ethyl]-3-oxo-butyramide (10 g) in toluene (800 ml) was added at 20° C. ammonium acetate (10 g) and the reaction was heated for 20 h at 100° C. in a Dean Stark system. The mixture was concentrated in vacuo and the product obtained was used without further purification in the following reaction step.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH3:40])[CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)O)C1C=CC=CC=1>C(#N)C.[PH2](O)=O>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]=1[OH:8])([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1ccccc1-c1cccc(C(O)(c2ccccc2)c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Agent: O=[PH2]O
Solvent: CC#N
Product: COc1ccccc1-c1cccc(C(c2ccccc2)c2cccc(C(C)(C)C)c2O)c1
Yield: 95.9 %

Procedure:
A solution of 29 (1.2 g, 2.27 mmol) in acetonitrile (70 mL) and 50% aqueous hypophosphorous acid (30 mL) was kept at reflux for 3.5 hr. The acetonitrile was removed in vacuo, the residue was diluted with ethyl acetate (150 mL) and water (100 mL). Phases were separated. The organic phase was washed with saturated sodium bicarbonate (2×100 mL) and water (100 mL), dried over sodium sulfate and filtered. The solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (45 g) with hexane (2 L) to yield pure D4 (0.92 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].Cl.[NH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1.C(N(CC)CC)C>>[CH:19]1([CH2:18][NH:17][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: NCC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1Cl
Yield: 75.7 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.2 mmol), aminomethyl cyclopropane hydrochloride (0.56 g, 5.2 mmol) and triethylamine (1.8mL, 12.9 mmol) were reacted to form the desired product (1.28 g, 84%). LC-MS m/z 325 (M+).
Reaction SMILES: C([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([F:17])=[C:11]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([F:17])=[C:11]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=1
Reactant: CC(C)(C)Nc1nc(NCc2ccccc2)c(C#N)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)Nc1nc(N)c(C#N)cc1F
Yield: 86 %

Procedure:
To 500 mg of 2-benzylamino-6-t-butylamino-3-cyano-5-fluoropyridine were added 3 ml acetic acid and 0.5 ml ethanol, and then, 10 microspatulas of palladium black, and the mixture was stirred under hydrogen atmosphere at 60° C. for 2 days. The catalyst was removed with a membrane filter, and the solvent of the filtrate was distilled off. To the residue was added chloroform, and the mixture was washed with aqueous solution of sodium hydrogencarbonate. The organic layer was collected, dried over magnesium sulfate. The solvent was distilled off to obtain 300 mg of the title compound.
Reaction SMILES: Cl.Cl.[CH:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]3[C:20]4[CH:28]=[C:27]([O:29]C)[C:26]([O:31]C)=[CH:25][C:21]=4[O:22][C:23](=[O:24])[C:16]=3[CH2:15]1)[CH2:4]2.[BrH:33]>>[BrH:33].[BrH:33].[CH:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]3[C:20]4[CH:28]=[C:27]([OH:29])[C:26]([OH:31])=[CH:25][C:21]=4[O:22][C:23](=[O:24])[C:16]=3[CH2:15]1)[CH2:4]2
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CC2CCC(CC2)C1)C3
Agent: Br
Agent: Cl
Product: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CC3CCC(CC3)C1)CC2

Procedure:
A solution of 3-[2-(3-azabicyclo[3.2.2]non-3-yl)ethyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one dihydrochloride (10.0 g, 0.020 moles) and 48% aqueous hydrobromic acid (100 ml) is stirred at reflux for 16 hours. The dihydrobromide product (10.7 g) is used as an intermediate without additional purification. A sample recrystallized from aqueous methanol/N,N-dimethylformamide had mp 270° C. (dec).
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=O)[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].C(=O)([O-])[O-].[NH4+].[NH4+].C([N:37](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.CO.ClCCl>[OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:28])[CH2:23][CH2:24][C:25]([NH2:37])=[O:27])[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC(=O)O)C1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)CCC(N)=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.2 %

Procedure:
To a mixture of 4-((3S)-3-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidin-1-yl)-4-oxobutanoic acid (35 mg, 0.087 mmol), ammonium carbonate (42 mg, 0.43 mmol), and triethylamine (18.2 μL, 0.130 mmol) in N,N-dimethylformamide (0.6 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (76.9 mg, 0.174 mmol). The resulting mixture was stirred at room temperature for 2.5 h. The mixture was diluted with ethyl acetate then washed with sat. NaHCO3, water, and brine. LCMS showed most of the desired product remained in the aqueous layer. The aqueous layer was concentrated to give white solids. The solids were stirred in ˜1:1 MeOH/dichloromethane and then filtered to give 40 mg crude product. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6 mg of the desired product. LCMS calculated for C19H24N5O3S (M+H)+: m/z=402.2. Found: 402.0.