Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][OH:25])[CH2:19]3)[C:6]=2[CH:5]=1.Cl[CH:27](Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:27][N:21]1[CH2:22][CH2:23][N:18]([C:7]2[C:6]3[CH:5]=[C:4]([CH3:3])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:19][C@@H:20]1[CH2:24][OH:25]
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CO)C1
Reactant: CC(Cl)Cl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CO)C1
Reaction time: 0.03 h

Procedure:
Add aqueous 37% formaldehyde (1.1 eqiv) to a solution of [(R)-4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-methanol (1 mmol) in dichloroethane (60 mL per 1 mmol non-alkylated starting material). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (1.5 mmol per 1 mmol non-alkylated starting material). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry over magnesium sulfate, filter and concentrate. Purify the residue via chromatography on silica gel (methylene chloride/methanol (90:10) affords the title compound as a yellow powder: mp 118-124° C.; 1H NMR (CDCl3) δ 2.31 (s, 3H), 2.43 (s, 3H), 2.45 (m, 1H), 2.59 (m, 1H), 2.82 (m, 1H), 3.31 (m, 1H), 3.58 (dd, 1H) 3.67-3.79 (m, 3H), 3.86 (dd, 1H), 4.96 (s, 1H), 6.30 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.96 (t, 1H), 7.01 (d, 1H); MS (APCI) m/z (rel intensity) 343 (100).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1)#[N:20].COCCOC>O>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@@:8]2([C:17]3[C:5](=[CH:4][CH:3]=[C:2]([C:23]4[CH:24]=[N:25][CH:26]=[C:21]([CH:22]=4)[C:19]#[N:20])[CH:18]=3)[CH2:6][CH2:7]2)[N:9]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Solvent: COCCOC
Solvent: O
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CC3)N=C(N)OCC2(F)F)c1

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 5-cyanopyridin-3-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound as an off-white solid.
Reaction SMILES: ClN1[C:7]2=[C:8]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[NH:9][N:10]([CH3:11])[C:6]2=CN(C)C1.ClC1[N:27]=[CH:26][N:25]=[C:24]2[N:28](C)N=C(C3OC([N+]([O-])=O)=CC=3)[C:23]=12>>[NH2:27][C:26]1[N:25]=[C:24]([CH3:23])[N:28]=[C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:7]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: CN1C=C2C(=C(c3ccc([N+](=O)[O-])o3)NN2C)N(Cl)C1
Product: Cc1nc(N)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1

Procedure:
The procedure described in Example 3b was repeated using 4-chloro-1,6-dimethyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4]pyrimidine as starting material instead of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, the reaction conditions being the same. The crystalline product was collected, washed with water and dried. Recrystallisation from dimethyl formamide gave 4-amino-1,6-dimethyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having decomposition point > 300°C. identical with the product obtained in Example 2.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl[S:13]([C:16]1[CH:17]=[C:18]([C:28]([OH:30])=[O:29])[C:19]2[O:23][CH:22]([CH3:24])[CH2:21][C:20]=2[C:25]=1[O:26][CH3:27])(=[O:15])=[O:14].C(=O)=O.[OH-].[Na+].[CH2:36](I)[CH3:37]>C(O)C.O>[CH2:36]([S:13]([C:16]1[CH:17]=[C:18]([C:28]([OH:30])=[O:29])[C:19]2[O:23][CH:22]([CH3:24])[CH2:21][C:20]=2[C:25]=1[O:26][CH3:27])(=[O:15])=[O:14])[CH3:37]
Reactant: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1CC(C)O2
Reactant: CCI
Agent: O=C([O-])O
Agent: O=C=O
Agent: O=S([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)c1cc(C(=O)O)c2c(c1OC)CC(C)O2
Temperature: 70 °C

Procedure:
220 ml of water, 47 g of sodium sulphite and 62.5 g of sodium bicarbonate were introduced into a 2-liter round-bottomed flask and the contents were then heated to 70° C. 76 g of 5-chlorosulphonyl-4-methoxy-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added in small amounts. Heating was maintained at 70°-80° C. for 1 hour 30 minutes, until the evolution of carbon dioxide was complete. The contents were then cooled to 20° C. and 256 ml of ethanol, 49.5 ml of 30% sodium hydroxide and 116 g of ethyl iodide were then added. The contents were heated under reflux for 30 hours, the losses of ethyl iodide being replenished and the pH being readjusted by adding sodium hydroxide as soon as the medium was no longer alkaline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN1CCCC1=O.[Cu](Br)Br>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[CH:10]=[C:9]2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccnc2[nH]c(-c3ccncc3)cc12
Reactant: Fc1ccc(Br)cc1
Agent: Br[Cu]Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccnc2c1cc(-c1ccncc1)n2-c1ccc(F)cc1
Temperature: 180 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
To a solution of 4-methyl-2-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (0.3 g, 1.43 mmol) in N-methylpyrrolidone (5 ml) was added 4-bromofluorobenzene (0.57 ml, 5.2 mmol), copper bromide (0.205 g, 1.43 mmol) and sodium carbonate (0.15 g, 1.43 mmol) and the reaction mixture was heated to 180° C. under argon. After 24 h, the reaction mixture was cooled and poured into 10% hydrochloric acid (50 ml). The solution was filtered through Celite® and the filtrate was neutralized to pH 7 with 10% sodium hydroxide. The solid was filtered off, dissolved in 80% methanol:methylene chloride and purified by preparatory thin layer chromatography to give 1-(4-fluorophenyl)-4-methyl-2-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (0.03 g) as a tan solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:33]=[CH:32][C:22]([C:23](=[O:31])[NH:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:21][CH:20]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]([F:34])([F:35])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:31])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of 26.4 g. of ethyl 4-[15-(trifluoromethyl)pentadecylamino]hippurate, 110 ml. of 1 N sodium hydroxide solution; and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6 N hydrochloric acid, and filtered. The solid is dried in vacuo and recrystallized from acetone to yield the product as a white solid.
Reaction SMILES: S1C=CN=[CH:2]1.[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([CH2:28]C)[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12.BrC(C)C(=O)C>>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][C:25]([CH3:2])=[C:26]([CH3:28])[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12
Reactant: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Reactant: c1cscn1
Agent: CC(=O)C(C)Br
Product: Cc1nc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)sc1C
Reaction time: 24 h

Procedure:
The procedure for thiazole synthesis, described in the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine, was employed with the exception that 3-bromo-2-butanone (0.183 g, 1.21 mmol) was used as the alkylating agent, and the alkylation reaction was conducted at 40° C. for 24 h. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.7-7.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4,5-dimethyl-1,3-thiazol-2-amine as an off-white powder (0.069 g, 0.133 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 6.83 min; MS (MH)+ 518.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.C(Cl)(Cl)Cl>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: NCCc1ccccn1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a 0° solution of 2.54 g of 2-(2-aminoethyl)pyridine, 50 ml of methylene chloride and 6.42 ml of pyridine is added, dropwise, 7.0 g of product from Example 3 in 250 ml of methylene chloride. The reaction is stirred at 0° C. for 2 hours followed by 14 hours at room temperature. The reaction is diluted with chloroform, washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:75-100% ethyl acetate/hexane) to give 3.58 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH:33]([CH3:35])[CH3:34]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:27])[F:28])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:33]([CH3:35])[CH3:34])[N:18]=2)=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1n[nH]c2c(C(F)(F)F)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)c2ccc(OCc3ccccc3)cc2)c2cccc(C(F)(F)F)c21
Temperature: 50 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of [4-(benzyloxy)phenyl](7-trifluoromethyl-1H-indazol-3-yl)methanone (0.20 g, 0.5 mmol) in 3 mL DMF was added in one portion sodium hydride (0.020 g, 0.5 mmol, 60% in oil). After the gas evolution ceased, 2-iodopropane (0.075 mL, 0.75 mmol) was added and the reaction was stirred at ambient to 50° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo provided 0.18 g of the title compound which was used directly in the following step.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]2[O:16][CH:3]12)=[N:10][O:11][N+:12]=3[O-].P(OCC)(OCC)OCC>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]2[O:16][CH:3]12)=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3c(cc2C2OC21)no[n+]3[O-]
Agent: CCOP(OCC)OCC
Solvent: c1ccccc1
Product: CC1(C)Oc2cc3nonc3cc2C2OC21
Reaction time: 0.25 h

Procedure:
1.00 g (4.27 mmol) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano[2,3-f]benz-2,1,3-oxadiazole-3-oxide (compound [G]) and 6 ml of benzene were stirred at 60° C., while 0.80 ml (4.70 mmol) of triethyl phosphite was added thereto dropwise within 15 minutes. Next, the obtained mixture was stirred for three hours.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)n3nccc3n2)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)C1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl 3-(7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-1-carboxylate (3.70 g, 12.0 mmol) and dimethylaniline (4.0 mL, 30 mml) was added phosphoryl trichloride (40 mL). The mixture was heated at 50° C. for 5 h and concentrated in vacuo. The residue was diluted with methylene chloride (100 mL) and quenched with saturated NaHCO3 (100 mL). The mixture was separated and the aqueous layer was extracted with chloride (100 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Biotage (CH2Cl2/EtOAc, 20:1 to 4:1). LC/MS RT=2.09 min (5 min method). Mass calculated for, M+H 322.12, observed 337.14.
Reaction SMILES: COC1C=CC(OC)=CC=1C(=O)CN1C(C(OCC)=O)=CC(C2C=NC=CC=2)=N1.[CH3:30][Si:31]([CH3:43])([CH3:42])[C:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34][N:33]=1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[CH2:49]Cl>>[CH3:57][O:56][C:52]1[CH:51]=[C:48]([CH:47]=[C:46]([O:45][CH3:44])[C:53]=1[O:54][CH3:55])[CH2:49][N:34]1[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:32]([Si:31]([CH3:42])([CH3:43])[CH3:30])=[N:33]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Agent: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Product: CCOC(=O)c1cc([Si](C)(C)C)nn1Cc1cc(OC)c(OC)c(OC)c1

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 3,4,5-trimethoxy benzyl chloride (purchased from Aldrich). 1H-NMR δ 6.98 (s, 1H), 6.21 (s, 2H), 5.44 (s, 2H), 4.41 (q, 2H), 3.81 (s, 3H), 3.76 (s, 6H), 1.40 (t, 3H), 0.22 (s, 9). Calculated mass for C19H28N2O5Si, 392.18, observed, 393.0 (M+1), 415.1 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].CS(C)=O.[CH3:23][CH:24]([C@H:26]1[CH2:31][NH:30][CH2:29][CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:25]>C1COCC1.CCOC(C)=O.O>[CH3:25][CH:24]([C@H:26]1[CH2:31][N:30]([C:7]2[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:29][CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH3:23]
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Yield: 59.6 %

Procedure:
4-Fluoro-2-(methyloxy)-1-nitrobenzene (Example 22, step A) (0.429 g, 2.51 mmol), and K2CO3 (0.410 g, 2.97 mmol) were placed in a flask with 14 mL of DMSO and stirred with a stir bar. 1,1-Dimethylethyl (2S)-2-(1-methylethyl)-1-piperazinecarboxylate (0.521 g, 2.28 mmol) was dissolved in 6.6 mL of THF and added via syringe. The mixture was stirred for 8 days and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded the title compound of step D (0.515 g, 1.36 mmol, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=9.3 Hz, 1H), 6.54 (dd, J=9.4, 2.3 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.01 (d, J=13.5 Hz, 1H), 3.86 (s, 5H), 3.60-3.75 (m, 1H), 3.22-3.28 (m, 1H), 3.06 (dd, J=13.6, 3.7 Hz, 1H), 2.90-3.02 (m, 1H), 1.79-1.92 (m, 1H), 1.37 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H).
Reaction SMILES: C([N:9]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[S:12])(=O)C1C=CC=CC=1.S(=O)(=O)(O)O.C(OCC(C)C)(=O)C.[OH-].[Na+]>O.C(O)(=O)C>[C:17]1([C@@H:15]2[CH2:16][NH:9][C@H:10]([C:11]([OH:13])=[S:12])[CH2:14]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)N1C[C@@H](c2ccccc2)C[C@H]1C(O)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OCC(C)C
Product: OC(=S)[C@@H]1C[C@H](c2ccccc2)CN1
Temperature: 25 °C

Procedure:
The N-benzoyl-cis-4-phenylthio-L-proline is heated on a steam bath and 0.5 liters of glacial acetic acid are added. The mixture is swirled and 0.5 liters of water followed by 100 ml. of concentrated sulfuric acid are added. The turbid mixture is heated at reflux at an oil bath temperature of about 125° and maintained at reflux until the reaction is completed. The reaction liquid is cooled to room temperature and 0.75 liters of isobutyl acetate and 3 kg. of cracked ice are added with brisk agitation. 50 g. of concentrated aqueous sodium hydroxide solution are added and the product is collected and washed with methanol. The product is further purified by dissolution in aqueous sodium hydroxide, treatment with activated carbon, filtration, and careful crystallization with HCl. The crystals are collected, washed with water, and dried to yield cis-4-phenyl-thio-L-proline as a white crystalline powder; m.p. 240° (d); [α]D23 -118° (C=1, N sodium hydroxide).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.O.C(O)(=O)C.[CH:17](N)=[NH:18]>COCCO>[F:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:17][NH:18][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: Nc1cnc(F)cc1C(=O)O
Reactant: N=CN
Solvent: O
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cnc(F)cc12

Procedure:
A suspension of 39.0 g (246 mmol) of 5-amino-2-fluoropyridine-4-carboxylic acid hydrated with 0.15 equivalents of water, 52.01 g (500 mmol) of formamidine acetate, and 500 mL of 2-methoxyethanol was heated at reflux for 6 hours, then concentrated to a solid. The solids were treated carefully with 100 mL of 10% aqueous sodium bicarbonate while maintaining vigorous stirring. The resultant suspension was filtered, and the collected brown solids were washed well with water, then dried over P2O5 to afford 31.3 g (77%,) of product that was used directly in the next reaction. Recrystallization of a small sample from methanol gave product of mp 287° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]=[N+:19]=[N-:20])(=[O:14])[CH3:13]>>[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]1[CH:11]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[N:20]=[N:19]1)(=[O:14])[CH3:13]
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Reactant: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Product: CC(=O)OC(COS(=O)(=O)c1ccc(C)cc1)Cn1cc(Cn2ccnc2[N+](=O)[O-])nn1

Procedure:
2-Nitro-1-(prop-2-ynyl)-1H-imidazole 10 (0.2 g, 1.32 mmol) is heated with 1-azido-3-(tosyloxy)propan-2-yl acetate 15 (0.41 g, 1.32 mmol) at 60° C. overnight. The residue is purified by chromatography on silica gel (MeOH/CH2Cl2, 1:10) to afford 16.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12].C(=O)(O)[O-].[Na+].[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[CH2:19][Br:18])=[C:3]([Cl:12])[CH:4]=1)(=[O:9])=[O:10]
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 750 mg (3.63 mmol) of 4-amino-3-chlorobenzenesulfonamide (A-2) and 610 mg (7.26 mmol) of sodium bicarbonate in 25 mL of CH2Cl2 was stirred at room temperature for 18 hours. Bromoacetyl bromide (A-1) was then added, and the mixture was stirred for an additional 12 hours. The mixture was then concentrated in vacuo to a yellow oil. The oil was washed with three 25 mL portions of diethyl ether, decanted, and concentrated in vacuo to give the desired product A-3 as a tan solid. MS: M+1=329.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]#[N:17])([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]#[N:17])([CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CO)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 537 mg of 1-(tert-butoxycarbonyl)-4-cyano-4-(hydroxymethyl)piperidine in 100 ml of tetrahydrofuran, 0.4 ml of triethylamine was added and the solution was cooled to 0° C. 0.2 ml of methanesulfonyl chloride was added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After adding water to the residue, extraction was performed with ethyl acetate. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (799 mg, 100% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][N:6]=[CH:5]2.[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[O:19])=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[Cl:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][C:14]=3[CH3:13])[C:18]([NH:20][C:21]3[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=3)=[O:19])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)Nc2ccnn2C)cc1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: COCCOC
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccc2c(Cl)nncc2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a 150 mL round-bottomed flask was added 6-bromo-1-chlorophthalazine (18, 357 mg, 1465 μmol), tetrakis(triphenylphosphine)palladium (84.7 mg, 73.3 μmol), 4-methyl-N-(1-methyl-1H-pyrazol-5-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (500 mg, 1465 μmol), sodium carbonate (466 mg, 4396 μmol). The reagents were dissolved in DME:water mixture (15 mL, 4:1). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was evaporated and residue dissolved in ethyl acetate (20 mL) and washed with water (2×20 mL) and dried over MgSO4 and rotovaped to yield the title compound 24 as a crude product. The crude product 24 was adsorbed on silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 65% to 80% EtOAc in DCM, to provide 3-(1-chlorophthalazin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide (24).