Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:32][C:33]1[CH:38]=[C:37]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:22])=[O:23])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(N)c3)c2c1
Yield: 26.6 %

Procedure:
N-[3-(3-Aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 276 mg of 3-aminophenylboronic acid, 20 ml of dimethylformamide, 1.6 ml of a saturated aqueous sodium hydrogencarbonate solution and 25 mg of tetrakis(triphenylphosphine)palladium[0]. 102 mg of N-[3-(3-aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 220° C. (analysis C20H18N4O4S2 % calculated C, 54.29; H, 4.10; N, 12.66; O, 14.46; S, 14.49. % found C, 53.48H, 4.11; N, 12.50; S, 13.95).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O.CO>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][CH:38]=4)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(C)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
Diethyl azodicarboxylate (DEAD) (139 μL, 0.88 mmol) was added dropwise to a solution of 5,11-dihydro-2,5-dimethyl-11-ethyl-8-(2-hydroxyethyl)-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (110 mg, 0.35 mmol), 4-hydroxyquinoline (128 mg, 0.88 mmol) and Ph3P (231 mg, 0.88 mmol) in THF (3.5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted in EtOAc (60 mL) and the solution was successively washed with 1 N aqueous NaOH (3×10 mL) and brine (15 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc then EtOAc:MeOH, 9.5:0.5) to give the title compound (57 mg, 37% yield) as a white solid: MS (ESI) m/z 440 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]([P:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[O-:7])=[O:5].[Na+]>O.S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:3]=1[C:4]([P:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])[OH:8])=[O:5]
Reactant: Cc1cc(C)c(C(=O)P(=O)([O-])c2ccccc2)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(C(=O)P(=O)(O)c2ccccc2)c(C)c1

Procedure:
46.5 parts by weight of the sodium salt of Example 1 were dissolved in 300 parts by weight of water, and 150 parts by volume of 1N sulfuric acid were added. The resulting precipitate was filtered off under suction, washed with water and dried, and 38.9 parts by weight of product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:24])[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:37]1[CH:46]=[CH:45][C:44]2[N:43]([CH3:47])[C:42](=[O:48])[CH:41]=[C:40]3[C:49]4[C:54]([C:55](=[O:56])[C:38]=1[C:39]=23)=[CH:53][CH:52]=[CH:51][CH:50]=4>CO.ClC1C=CC=CC=1Cl>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:7]1[C:6](=[O:24])[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37]3[CH:46]=[CH:45][C:44]4[N:43]([CH3:47])[C:42](=[O:48])[CH:41]=[C:40]5[C:49]6[C:54]([C:55](=[O:56])[C:38]=3[C:39]=45)=[CH:53][CH:52]=[CH:51][CH:50]=6)=[C:13]3[C:14]=2[C:9](=[CH:10][CH:11]=[CH:12]3)[C:8]1=[O:15]
Reactant: Cc1ccc(N2C(=O)c3cccc4c(N)ccc(c34)C2=O)c(C)c1
Reactant: Cn1c(=O)cc2c3c(c(Br)ccc31)C(=O)c1ccccc1-2
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N2C(=O)c3cccc4c(Nc5ccc6c7c(cc(=O)n6C)-c6ccccc6C(=O)c57)ccc(c34)C2=O)c(C)c1
Temperature: 120 °C

Procedure:
To a three-necked round-bottomed flask equipped with a thermometer and a Dean-Stark apparatus was charged 6-amino-2-(2,4-dimethylphenyl)benzo[de]isoquinoline-1,3-dione (4.69 g), potassium acetate (1.443 g), potassium carbonate (2.032 g), cupric acetate (0.1262 g), cupric iodide (0.120 g), and ortho-dichlorobenzene (45 ml) to obtain a mixture. The mixture was heated to 120° C. in about 10 minutes. After being maintained at 120° C. for about 30 minutes, 6-bromo-3-methyl-3H-naphtho[1,2,3-de]quinoline-2,7-dione (5 g) and ortho-dichlorobenzene (45 ml) were added to the mixture. Then the temperature of the resulting reaction mixture was raised to 165° C. over a period of about 1.5 hours. After being maintained at this temperature for about 4 hours, formation of a red solid was observed. A portion of the reaction mixture was spotted on a TLC plate and viewed under ultraviolet radiation to monitor the disappearance of the starting materials 6-amino-2-(2,4-dimethyl)phenyl-benzo[de]isoquinoline-1,3-dione and 6-bromo-3-methyl-3H-naphtho[1,2,3-de]quinoline-2,7-dione. After being heated for 2 more hours at the same temperature, TLC analysis of the reaction mixture indicated the absence of both the starting materials. The reaction mixture was then cooled, poured into 175 ml of methanol, filtered, and the filter cake was washed with 2 to 3 100 ml portions of methanol to give the desired product in a yield of 7.2 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=O)=CC=1.[S:56]1[C:60]([CH2:61]O)=[CH:59][C:58]2[CH:63]=[CH:64][CH:65]=[CH:66][C:57]1=2>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:61][C:60]2[S:56][C:57]3[CH:66]=[CH:65][CH:64]=[CH:63][C:58]=3[CH:59]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[N:10]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Agent: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2cc3ccccc3s2)NS(=O)(=O)c2cccnc2)n1
Yield: 93.1 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (126 mg, 0.263 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using benzo[b]thiophen-2-ylmethanol (43.2 mg, 0.263 mmol) in place of tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (153 mg) as a slightly yellow liquid. (Yield: 93%)
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:59])[C:56]([F:58])([F:57])[CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C:56]([F:58])([F:57])[C:52]([F:59])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: FC1(F)CNCC1(F)F
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3,4,4-tetrafluoropyrrolidine hydrochloride and isolated as light-yellow gum (12.6 mg, 60%). MS(m/e): 443.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:21][CH3:24])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
790 mg tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate are placed in 5 ml dimethylformamide and 193 mg sodium hydride (60% in mineral oil) are added. The reaction mixture is stirred for 30 min at ambient temperature, then 267 μl methyl iodide are added. After 1 h the reaction mixture is poured onto ice and the product is extracted with diethyl ether. 650 mg product are obtained in the form of an oil. Analytical HPLC-MS (method B): RT==1.88 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=O)[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=N1.N1CCCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[N:25]1([C:19]([C:18]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:14][C:13]=3[CH:15]=[CH:16][CH:17]=2)=[O:21])[CH2:26][CH2:31][CH2:30][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carboxylic acid (40.0 mg, 0.136 mmol), 1-hydroxybenzotriazole (18.4 mg, 0.136 mmol) and pyrrolidine (0.017 ml, 0.204 mmol) in DMF (1 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52.2 mg, 0.272 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (42.0 mg, 89.2%) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:39])[C@H:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:30])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:39])[C@H:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:30])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:14]=2)[CH2:9]1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-Benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester in MeOH (˜0.5M) is treated with an equal volume of 4M HCl in dioxane and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by column chromatography/crystallisation to afford the title compound.
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH:20]=1)[NH2:19]>CN(C=O)C>[NH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][O:10][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH:20]=1)[NH2:19]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(OC[C@H](N)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
(R)-(−)-2-Phenylglycinol (5.043 g, 36.8 mmol) was placed in a 250-mL RBF and placed under a nitrogen atmosphere. DMF (100 mL) was added and the reaction was stirred until a clear, colourless solution resulted. NaH (2.206 g, 55.1 mmol) was then added, followed by DMF (10 mL) as a wash, producing a vigorous reaction (gas evolution). The reaction was stirred at room temperature until the gas evolution had subsided, leaving a reddish heterogeneous mixture. 5-Fluoro-2-nitroaniline (6.89 g, 44.1 mmol) was then added, followed by DMF (10 mL), which immediately produced a bright red colour. The reaction was left stirring at room temperature and monitored by LC-MS. The reaction was quenched by its addition to an Erlenmeyer flask containing ethyl acetate (200 mL) and dilute aqueous NaHCO3 (250 mL). The phases were separated in a separatory funnel, and the organic layer was washed with water (150 mL), then brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was then purified by silica gel column (5-75% EtOAc in n-heptane), yielding two fractions of high purity 5-[(2R)-2-amino-2-phenylethoxy]-2-nitroaniline, both contaminated with residual DMF, as a yellow-orange oil. LRMS (ESI) calc'd for (C14H16N3O3) [M+H]+, 274.1; found 274.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[Cl:9].C([Sn](CCCC)(CCCC)OC)CCC.CC(=C)[CH2:27][C:28](=[O:30])[CH3:29].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>Cl[Pd]Cl.C1(C)C=CC=CC=1>[Cl:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:27][C:28](=[O:30])[CH3:29]
Reactant: Cc1cccc(Br)c1Cl
Reactant: C=C(C)CC(C)=O
Agent: Cl[Pd]Cl
Agent: CCCC[Sn](CCCC)(CCCC)OC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc(C)c1Cl
Temperature: 100 °C
Yield: 80 %

Procedure:
A Smith process vial was charged with 1-bromo-2-chloro-3-methylbenzene (528 mg, 2.57 mmol, 1 eq.), tributylmethoxytin (1.11 mL, 1.5 eq.), 4-methylpent-4-en-2-one (0.42 mL, 1.5 eq.), PdCl2 (23 mg, 5%) and tri(o-tolyl)phosphine (79 mg, 10%), toluene (1 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in oil bath at 100° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to 1-(2-chloro-3-methylphenyl)propan-2-one (375 mg, 80% yield). 1H-NMR: 400 MHz, (CDCl3) δ: 7.19-7.02 (m, 3H), 3.82 (s, 2H), 2.38 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH3:13]>CO>[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([CH2:10][NH2:11])([CH3:9])[CH2:6][CH:4]([NH2:13])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Reactant: N
Solvent: CO
Product: CC1(C)CC(N)CC(C)(CN)C1
Yield: 92.1 %

Procedure:
A solution containing 15 wt. % of IPN, 30 wt. % of ammonia and 55 wt. % of methanol was produced and stirred in a pressure vessel under the pressure obtained for 24 h at 25° C.; in this case isophorone nitrile (IPN) was converted largely into isophorone imino nitrile (IPIN). This solution was then pumped at 400 ml/h, corresponding to an LHSV value of 2 h-1, through the reactor, which was filled with 160 ml of hydrogenation catalyst according to the invention (as in Example 1) and 40 ml of inert steel balls. According to the analysis of the product mixture a yield of 92.1% of IPDA was obtained. After distillation of the product mixture a product purity of 99.78% IPDA was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[NH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:39][CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([S:48]([NH2:51])(=[O:49])=[O:50])=[CH:46][CH:47]=2)=[N:13]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NS(=O)(=O)c1ccc(CCNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 35 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-(2-aminoethyl) benzenesulfonamide and potassium carbonate essentially as described above in example 4 except that the column is eluted using a graded solvent mixture of dichloromethane:methanol (90:10). Combine the appropriate fractions and concentrate to give the title compound (0.16 g, 35% Yield) as a solid. Purity by LC/MS (APCI)=96% area, [M+H]+=458 m/e.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cc(-n2cnnn2)ccc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(-n2cnnn2)ccc1Cl
Reaction time: 20 h

Procedure:
A solution of 1.0 g of 2-chloro-5-(1-tetrazolyl)benzoic acid from Step A in 25 mL of methanol was saturated with HCl (gas) and stirred for 20 h. The solution was concentrated in vacuo, diluted with water and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to afford 1.0 g of title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([O:40]C)=[O:39].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([OH:40])=[O:39]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(C)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(N2CCN(c3cccc(C)c3)CC2)=Nc2c(F)cccc2C1CC(=O)O

Procedure:
In 40 ml of dioxane, 892 mg (1.56 mmol) of methyl {8-fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 33A) and 187.6 mg (4.69 mmol) of sodium hydroxide are stirred at 50° C. for 2 hours. Following removal of the solvent, the residue is taken up in water and adjusted to pH 4-5 using 1N hydrochloric acid. The product is filtered off and then washed with water and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:23]1[CH2:28][CH2:27][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:27][CH2:28]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CC(OCCN2CCOCC2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCOCC2)CC1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1)(0.2 g, 0.67 mmol), 4-(2-(piperidin-4-yloxy)ethyl)morpholine (79) (0.144 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (0.055 g, 16.6% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.60-1.48 (1H, m), 1.83-1.64 (2H, m), 1.94-1.88 (1H, m), 2.59-2.57 (4H, m), 2.64 (2H, t), 3.14-3.05 (1H, m), 3.49-3.37 (1H, m), 3.58-3.51 (1H, m), 3.66-3.60 (3H, m), 3.74-3.72 (4H, m), 4.06-3.94 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.32-7.26 (2H, m), 7.77-7.70 (3H, m), 8.48-8.44 (1H, m), 10.77 (1H, s); m/z (LC-MS, ESI+), RT=1.57 (M+H 495).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1>CCO.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: NCc1ccc(Cl)nc1Cl
Yield: 81.9 %

Procedure:
In a mixture of 50 ml EtOH and 20 ml DMF was dissolved 3.1 g (0.01 mole) of N-(2,6-dichloro-3-pyridylmethyl)phthalimide under heating, followed by addition of 0.75 g (0.015 mole) of H2NNH2 ·H2O under reflux. After 1 hour of refluxing, EtOH and DMF were distilled off. To the residue were added 10 ml of concentrated hydrochloric acid and 5 ml of water, and the mixture was refluxed for 30 minutes. The resulting crystals were filtered off and the filtrate was neutralized with NaHCO3 and extracted with CH2Cl2 (30 ml×3). The extract was dried over MGSO4 and the solvent was distilled off to give 1.45 g of the title compound as a yellow oil.