Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][NH2:10])[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[C:18](=[CH2:21])[C:19]#[N:20]>O.CO>[NH2:20][C:19]1[N:9]([CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[N:10]=[CH:21][CH:18]=1
Reactant: NNC1CN2CCC1CC2
Reactant: C=C(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1ccnn1C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Quinuclidinyl-hydrazine (D2) (5.0 g, 35.5 mmol) was added to a solution of K2CO3 (4.90 g, 35.5 mmol) in water (13 ml) and the ice-cooled solution was stirred vigorously while 2-chloroacrylonitrile (3.10 g, 2.83 ml, 35.5 mmol) was added dropwise over 1 minute. The solution was then stirred at room temperature overnight. The mixture was diluted with MeOH, evaporated to a slurry under reduced pressure, suspended in saturated aqueous potassium carbonate and extracted with EtOAc (3×100 ml), followed by CHCl3 (4×250 ml). The organic extracts were dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to yield a brown oil, which was purified by column chromatography (neutral alumina eluting with chloroform), to yield a faster running fraction (E3) (44 mg) and a slower running fraction (E4) (32 mg). Both were crystallised separately by trituration with diethyl ether, to yield white crystalline solids.
Reaction SMILES: [C:1]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][CH:23]1[CH:27]=[CH:26][CH:25]([CH3:28])[NH:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[C:1]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([N:24]1[CH:25]([CH3:28])[CH:26]=[CH:27][CH:23]1[CH3:22])=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1C=CC(C)N1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C=CC(C)N1C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
2.1 g of 2-[(N-Boc)amino]-3-(4-cyanophenyl)-propionic acid are mixed with 0.715 g of 2,5-dimethyl-2,5-dihydropyrrole in 10 ml of DMF, 3.9 g of BOP are added and the pH is adjusted to 7 by addition of Et3N. After stirring for 18 hours at RT, the mixture is evaporated to dryness and is then taken up in EtOAc, washed with NaHCO3 solution, with KHSO4/K2SO4 and with saturated NaCl solution. The resulting solution is dried over Na2SO4 and then evaporated. The residue is taken up in an ether/hexane mixture and then dried over Na2SO4. 1.4 g of the expected compound are obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Yield: 97 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 97% of theory, C26H26N6O3 (470.5) ##EQU39##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[NH:39][C:40]([CH:43]6[CH2:47][CH2:46][CH2:45][N:44]6[C:48](=[O:61])[CH:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[N:41][CH:42]=5)=[CH:34][CH:33]=4)[CH:28]=3)[CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:63][O:64]C(NC(C1C=CC=CC=1OC)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:32]4[CH:33]=[CH:34][C:35]([C:38]5[NH:39][C:40]([CH:43]6[CH2:47][CH2:46][CH2:45][N:44]6[C:48](=[O:61])[CH:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=6[O:64][CH3:63])=[N:41][CH:42]=5)=[CH:36][CH:37]=4)[CH:28]=3)[CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1OC
Reactant: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)c7ccccc7)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Product: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)c7ccccc7OC)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Yield: 23 %

Procedure:
This compound was synthesized using the same method used to synthesize [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid (0.020 g, 0.082 mmol) giving {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-4-methylene-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.011 g, 23% yield) as a white solid. LCMS-ESI+: calc'd for C49H52N8O7: 864.40 (Me); Found: 865.35 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]2.Br>>[C:12]1([CH:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=3)[CH2:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc2c(c1)CC(c1ccccc1)C2
Agent: Br
Product: Oc1ccc2c(c1)CC(c1ccccc1)C2
Temperature: 25 °C

Procedure:
Mixture of 5-methoxy-2-phenylindane (200 mg) and concentrated HBr (4 ml) was refluxed for 5.5 h. Reaction mixture was allowed to cool to room temperature and 20 ml of ice water and it was extracted with methylenechloride. The combined organic layers were washed with brine and dried with Na2SO4. The solvents were evaporated to give 2-phenylindan-5-ol. 1H-NMR (400 MHz, d6-DMSO): 9.05 (bs, 1H), 7.3-7.28 (m, 4H), 7.26-7.15 (m, 1H), 7.0 (d, 1H, J 8.1 Hz), 6.64 (d, 1H, J 1.9 Hz), 6.55 (dd, 1H, J 1.9, 8.1 Hz), 3.60 (k, 1H, J 8.6 Hz), 3.18 (m, 2H), 2.86 (dt, 2H, J 8.6, 16 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][C:5]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([NH:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=3)=[O:17])[CH:13]=2)=[CH:4][N:3]=1
Reactant: NCc1ccc(N)cc1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCc3ccc(N)cc3)c2)cnc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.1 %

Procedure:
A solution of 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}benzoic acid (0.10 g, 0.37 mmol), HOBt (0.055 g, 0.41 mmol) and HBTU (0.15 g, 0.41 mmol) in DMF (1.2 mL) was stirred at r.t. for 10 min. A solution of [4-(aminomethyl)phenyl]amine (0.050 mL, 0.44 mmol) in DMF (1.0 mL) was added and the resulting solution was stirred for 12 h at r.t. The solution was concentrated in vacuo and the crude mixture was partitioned between EtOAc (100 mL) and brine (50 mL). The organic layer was washed with brine (2×50 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified via column chromatography (SiO2, 5% MeOH/CH2Cl2) and trituration of the product gave 0.035 g (39% yield) of product: 1H NMR (400 MHz, d6-DMSO): 8.95 (t, 1H), 8.91 (s, 1H), 8.84 (m, 1H), 8.50 (m, 1H), 8.37 (dt, 1H), 7.87 (dt, 1H), 7.56 (t, 1H), 7.01 (d, 2H), 6.52 (m, 2H), 4.97 (s, 2H), 4.35 (d, 2H), 2.85 (d, 3H); MS (EI) for C20H20N6O2: 377 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH3:30][CH2:31]O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][C:5]=1[C:6]([O:8][CH2:30][CH3:31])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Yield: 65 %

Procedure:
A solution of 34A (4.5 g, 17.4 mmol) in EtOH (120 mL) was treated with concentrated H2SO4 (4 mL) and heated to reflux for 24 hours. The mixture was cooled to room temperature and neutralized with 5% NaHCO3. The resulting solution was extracted with CH2Cl2, dried (MgSO4), filtered, and concentrated to afford 43A (2.6 g, 65%).
Reaction SMILES: C([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.N>O1CCOCC1.Cl.O>[C:11]([C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1[OH:15])[CH2:4][NH2:3])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(CNC=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(CN)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 96.8 %

Procedure:
9.81 g (37.3 mmol) N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was dissolved in 24 mL dioxane and 7.2 mL concentrated hydrochloric acid. The mixture was heated to reflux for one hour. The mixture was allowed to cool down to room temperature and diluted with 50 mL water. The mixture was made alkaline, using a 10% ammonia solution. 3,5-di-tert.butyl-4-hydroxybenzyl amine precipitated from the medium, was isolated by filtration and dried. 8.5 g (97%) of 3,5-di-tert.butyl-4-hydroxybenzyl amine was isolated (m.p.: 159-9° C.). 3,5-di-tert.butyl-4-hydroxybenzyl amine has a tendency to lose ammonia upon heating, forming the corresponding di- and tribenzyl derivatives.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22]S(C4C=CC=CC=4)(=O)=O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:32]([F:35])([F:34])[F:33])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41].Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][Cl:36])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:32]([F:34])([F:35])[F:33])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NS(=O)(=O)c3ccccc3)cc2)cc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NC(=O)CCCCl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At a solution of N-[4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenylsulfonyl]benzensulfonamide (1 g, 2.262 mmol) in pyridine (50 ml) cooled at 0° C., 4-chlorobutyrylchloride was added dropwise (0.294 ml), the solution was maintained under stirring for 10 minutes at 0° C., the temperature was then raised to room temperature and the solution was maintained under stirring for 2 hours. Then HCl was added (50 ml, 0.1 N) and the mixture was extracted with CH2Cl2. The combined organic phases were washed with water, dried and the solvent was evaporated at reduced pressure. The crude compound as purified by chromatography on a silica gel column with n-hehan/ethyl acetate 8/2 as eluent to give 0.400 mg of product 4A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[N:23]=[C:22]([O:34][CH3:35])[N:21]=1>CN1CCCC1.O>[CH3:35][O:34][C:22]1[N:21]=[C:20]([NH:11][CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([CH3:13])[CH3:12])[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[N:23]=1
Reactant: COc1cccc(-c2cc(Cl)nc(OC)n2)c1
Reactant: COc1ccc(C(C)(C)CN)cc1
Agent: CN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(C)(C)CNc2cc(-c3cccc(OC)c3)nc(OC)n2)cc1
Temperature: 175 °C
Yield: 69.4 %

Procedure:
A mixture of 2-(4-methoxy-phenyl)-2-methyl-propylamine [172 mg, 0.96 mmol, Intermediate (35)], sodium bicarbonate (0.12 g), and 4-chloro-2-methoxy-6-(3-methoxy-phenyl)-pyrimidine [120 mg, 0.48 mmol, Intermediate (53)] in N-methylpyrrolidine (3 mL), is heated to 175° C. for 3 hours. The mixture is diluted with water, and extracted with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 30% EtOAc in heptane to afford [2-methoxy-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-2-methyl-propyl]-amine [131 mg, 69%, Example 29]. LCMS: RT=2.73 minutes, MS: 394 (M+H). 1H NMR (300 MHz, CDCl3): □7.59 (1H, s), 7.51 (1H, d, J=7.8 Hz), 7.35-7.27 (3H, m), 6.96 (1H, dd, J=8.1, 2.4 Hz), 6.88 (2H, d, J=9 Hz), 6.31 (1H, s), 4.02 (3H, s), 3.86 (3H, s), 3.79 (3H, s), 3.62 (2H, brs), 1.4 (6H, s). IC50=792 nM
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].Cl.[CH3:16][O:17][C:18](=[O:24])[C@@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20].CO.C(N(CC)CC)C>>[CH3:22][CH:21]([CH3:23])[C@@H:19]([N:20]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:18]([O:17][CH3:16])=[O:24]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-nitro-isochromen-1-one (5 g, 0.03 mol) and D-Valine methyl ester hydrochloride (5 g, 0.03 mol) were refluxed in methanol (40 mL, 1 mol) with triethylamine (5 g, 0.05 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g of silica gel, 0-30% EtOAc/Hexane) to yield a brown oil. MS m/z 305.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)C=Cc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C=Cc4ccccc4)cc23)CC1
Yield: 40.1 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol) cinnamic acid, 7.2 mg (40%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2nsnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2nsnc12

Procedure:
A mixture of 4-methyl-2,1,3-benzothiadiazole (6.0 g, 40 mmol) and N-bromosuccinimide (7.12 g, 40 mmol) in carbon tetrachloride (80 mL) was refluxed under irradiation with a sunlamp for 8 hours. After cooling with ice-water bath, the succinimide was filtered off and the filtrate was washed with saturated Na2S2O3, brine, dried over Na2SO4. After removal of solvent pure 4-bromomethyl-2,1,3-benzothiadiazole (8.8 g, 96%) was obtained as a light-yellow crystalline powder. Rf=0.45 (hexane/ethyl acetate=4:1); 1H NMR (200 MHz, CDCl3) δ5.00 (s, 2H), 7.57 (m, 2H), 7.98 (d, J1=8.5 Hz, J2=1.2 Hz, 1H); HRMS: Calcd. for C7H5BrN2S 227.9357, found 227.9395.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([O:20]C)=[O:19])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].O.O[Li].O>C1COCC1>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cn[nH]c2)cc2c1cnn2C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3cn[nH]c3)cc21
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a stirred solution of methyl 1-isopropyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylate (750 mg, 2.64 mmol) in THF:H2O (30 mL) was added LiOH.H2O (330 mg, 7.85 mmol) and the resulting mixture was refluxed at 80° C. for 8 h. THF was distilled off under reduced pressure and the aqueous layer was acidified with 10% HCl (to pH ˜5) at 0° C. The precipitated solid was collected by filtration and dried to afford the title compound 1-isopropyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylic acid as an off-white solid (540 mg, 76%). LCMS (ES+) m/z=271.09.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[S:5][C:6]=1[CH3:7].FC1(F)OC2C=C(C)C(C3N=C[C:25]([NH:28][C:29](=O)[C:30]4[CH:35]=[CH:34]C=CC=4F)=[N:26]C=3)=CC=2O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(#N)C.O>[CH3:7][C:6]1[S:5][C:4]2[CH2:8][CH2:9][CH2:10][CH2:11][C:3]=2[C:2]=1[C:30]1[CH:35]=[CH:34][C:25]([NH2:26])=[N:28][CH:29]=1
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Reactant: Cc1sc2c(c1Br)CCCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1sc2c(c1-c1ccc(N)nc1)CCCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
Palladium tetrakis-triphenylphosphine (12 mg, 10 μmol) was added to a degassed solution of bromide 239 (46 mg, 0.2 mmol) and boronate 11 (88 mg, 0.4 mmol) in dioxane:acetonitrile:water (9:9:2, 1.5 mL) and potassium phosphate (63 mg, 0.3 mmol). The resulting mixture was heated under argon at 90° C. with stirring for 4 hours. The mixture was then cooled, extracted with dichloromethane (3×10 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 240 (32 mg, 66%) as an oil: LRESIMS m/z 245.1 [M+H]+, calcd. for C14H17N2S1 245.1.
Reaction SMILES: Cl[O-].[Ca+2].Cl[O-].[NH2:6][C:7]([CH3:16])([CH2:10][C:11](OC)([CH3:13])[CH3:12])[C:8]#[N:9].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O.CO>[N:6]([C:7]([CH3:16])([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8]#[N:9])=[N:6][C:7]([CH3:16])([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8]#[N:9]
Reactant: COC(C)(C)CC(C)(N)C#N
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Reaction time: 0.75 h

Procedure:
To a mixture of 276 parts of methanol and 129 parts of 10% aqueous calcium hypochlorite at -10°C. are added with agitation 15.6 parts of 2-amino-4-methoxy-2,4-dimethylpentanonitrile. The mixture was stirred for approximately 45 minutes while the temperature was allowed to rise to 10°C. At this point in the reaction methanol constitutes 75 volume percent of the aqueous solvent. Titration with sodium thiosulfate as described in Example 1 showed 0.045 equivalent of oxidizing agents in the reaction mixture. The reaction mixture was then acidified to a pH of 3 with 10% hydrochloric acid and 2.16 grams (.0675 equivalent) of SO2 gas were added to the mixture, followed by 232 parts of water. The precipitated 2,2'-azobis (2,4-dimethylvaleronitrile), isolated by filtration, was found to be white and free-flowing and had a purity of 97.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([C:15]#[N:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.[C:20]([O:24][NH2:25])([CH3:23])([CH3:22])[CH3:21].N1CCCC1>C(O)CC>[C:20]([O:24]/[N:25]=[C:15](/[C:14]1[C:9]([C:7](=[O:8])[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:18])=[N:10][CH:11]=[CH:12][CH:13]=1)\[NH2:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)ON
Reactant: N#Cc1cccnc1C(=O)c1cc(Cl)ccc1O
Agent: Cl
Solvent: C1CCNC1
Solvent: CCCO
Product: CC(C)(C)O/N=C(\N)c1cccnc1C(=O)c1cc(Cl)ccc1O
Yield: 86 %

Procedure:
A mixture of 2-(5-chloro-2-hydroxybenzoyl)-3-cyanopyridine (217 mg), O-t-butylhydroxylamine hydrochloride (158 mg), pyrrolidine (149 mg) and n-propanol (4.0 ml) was heated for 30 minutes under reflux. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed successively with an aqueous solution of potassium hydrogensulfate and a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-chloro-2-hydroxybenzoyl)-3-carbamoylpyridine O-t-butyloxime (251 mg) (Compound 152).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH3:26])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCOc1cc(Br)ccc1O
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(Br)cc1OCC
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 4-bromo-2-ethoxyphenol (8.0 g) in DMF (50 ml) were added at room temperature potassium carbonate (7.65 g), sodium iodide (6.64 g) and 2-chloroethylpropylether (5.6 ml), and the mixture was stirred at 90° C. for 24 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N sodium hydroxide solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:4) to give yellow oil of 4-bromo-2-ethoxy-1-(2-propoxyethoxy)benzene (10.33 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH:18]=[O:19])[C:5]([NH:7][C:8]1[S:9][C:10]([S:13]([CH3:15])=[O:14])=[N:11][N:12]=1)=[O:6])[C:2]#[CH:3].Cl>O>[CH3:15][S:13]([C:10]1[S:9][C:8]([N:7]2[CH:18]([OH:19])[CH2:17][CH2:16][N:4]([CH2:1][C:2]#[CH:3])[C:5]2=[O:6])=[N:12][N:11]=1)=[O:14]
Reactant: C#CCN(CCC=O)C(=O)Nc1nnc(S(C)=O)s1
Agent: Cl
Solvent: O
Product: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-propargyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone.