Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([P:19]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])=[O:20])[CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[CH2:21]([P:19]([C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C@H:39]4[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]4)=[C:32]4[C:36]=3[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH:18]=[CH:17][CH:16]=1)([CH2:24][CH2:25][CH3:26])=[O:20])[CH2:22][CH3:23]
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Reactant: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c1
Product: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c1

Procedure:
The title product was prepared according to the procedure for Example 102 using 4-chloro-N-[3-(dipropylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (Compound 168B) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.33 Hz, 6H), 1.24-1.40 (m, 4H), 1.42-1.58 (m, 4H), 1.79 (d, J=12.88 Hz, 2H), 1.82-1.89 (m, 2H), 1.89-1.98 (m, 4H), 3.08 (s, 3H), 3.42-3.54 (m, 1H), 4.54 (s, 2H), 4.64 (br. s., 1H), 7.26 (br. s., 1H), 7.63-7.72 (m, 2H), 7.79 (d, J=6.57 Hz, 2H), 8.52 (s, 1H), 8.62 (br. s., 1H), 10.14 (s, 1H), 10.59 (br. s., 1H). MS (ES+): m/z=630.27 [MH+]. HPLC: tR=3.17 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
Into a solution of 4,5-difluoro-2-nitroaniline (3.7 g) in acetic acid (27 ml) was added bromine (6.8 g) dropwise at 50° to 56° C. and stirred for 2.5 hours. The reaction mixture was poured into ice water (60 ml) and the resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (4.7 g) as yellow prisms, mp 105° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]([C:9](=[O:14])[C@@H:10]([O:12][CH3:13])[CH3:11])[N:7]=[C:6]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:5]1.[N:29]#[C:30]Br.C(N(CC)CC)C>ClCCl>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:6]1[S:5][C:4]([CH2:3][CH2:2][NH:1][C:30]#[N:29])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:8]([C:9](=[O:14])[C@@H:10]([O:12][CH3:13])[CH3:11])[N:7]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCN)c1ccccc1
Reactant: N#CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCNC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-1-(2-(2-aminoethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one (34.5 mg, 0.0721 mmol) and cyanogen bromide (9.9 mg, 0.0938 mmol) in dichloromethane (1 mL) was slowly added triethylamine (25.5 mg, 0.252 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to provide the crude product that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@:3]([C:9]1[S:13][C:12]([S:14][C:15]2[CH:24]=[C:23]3[C:18]([C:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:20][C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)=[N:11][CH:10]=1)([OH:8])[CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:37])=[N-]>C1COCC1>[F:34][C:2]([F:1])([F:33])[C@:3]([C:9]1[S:13][C:12]([S:14][C:15]2[CH:24]=[C:23]3[C:18]([C:19]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)=[CH:20][C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)=[N:11][CH:10]=1)([OH:8])[CH2:4][C:5]([O:7][CH3:37])=[O:6]
Reactant: O=C(O)C[C@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)C[C@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F

Procedure:
To a solution of (3R)-4,4,4-trifluoro-3-(2-{[4-(4-fluorophenyl)-2-oxo-2H-chromen-7-yl]thio}-1,3-thiazol-5-yl)-3-hydroxybutanoic acid (see example 12, step 4b) (0.140 g, 0.27 mmol) in THF was added an ethereal solution of diazomethane until the evolution of gas was finished. The solvent was removed to yield 0.120 g of the crude title compound. 1H NMR (400 MHz, acetone-d6): δ 7.96 (s, 1H), 7.77 (m, 2H), 7.58 (m, 2H), 7.48 (d, 1H), 7.39 (t, 2H), 6.53, (s, 1H), 6.42 (s, 1H), 3.63 (s, 3H), 3.40 (d, 1H), 3.25 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1.[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOCC>[OH-].[Na+]>[CH2:9]([O:16][C:17]([NH:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1ccnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cn1ccnc1NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
2-Amino-1-methylimidazole hydrochloride (0.3 g) was dissolved in 1N sodium hydroxide solution (5 ml ). Benzyloxycarbonyl chloride (0.43 g) and ether (2 ml ) were added, and the mixture was stirred for 1 hour. The product was extracted with ethyl acetate, the extract was washed with water and aqueous saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Diethyl ether-hexane was added to the resulting residue for crystallization, and the crystals were separated by filtration. The crystals of 2-benzyloxycarbonylamino-1-methylimidazole thus obtained was dissolved in chloroform, and 4N hydrochloric acid-ethyl acetate (0.5 ml) was added to form its hydrochloric acid salt. The crude crystals thus obtained were washed with ether to give 2-benzyloxycarbonylamino-1-methylimidazole hydrochloride (0.2 g, Yield: 30% ) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(=O)O[CH2:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:9][CH2:10][CH2:11][CH2:12][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCCO1
Reactant: Oc1cccc(Br)c1
Product: Brc1ccc2c(c1)OCCCC2

Procedure:
m-Bromophenol was reacted with γ-butyrolactone in analogy to Example 17, paragraphs B, C and D, to give 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 5 h

Procedure:
A mixture of 5.0 of 6,7-dichloro-2-cyclohexyl-5-methoxybenzo[b]thiophene and 50 g of pyridine hydrochloride is stirred at 195° for 5 hrs. The cooled mixture is diluted with 250 ml of water and the resulting aqueous mixture is extracted with 3×250 ml ether. The organic layers are combined, washed with 150 ml of 2 N hydrochloric acid, 2×100 ml of water, dried over anhydrous magnesium sulfate and filtered. The solvent is removed and the residue is chromatographed on a sillical gel column using hexane and then 1:1 ether-hexane as eluting solvents. Evaporation of the eluents gives 3.2 g of 6,7-dichloro-2-cyclohexyl-5-hydroxybenzo[b]thiophene. Crystallization from pentane gives the analytical sample, mp 59°-60°.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20]C)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.Cl>O>[C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([OH:20])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(NCCOc2cccc3ccccc23)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(NCCOc2cccc3ccccc23)c1

Procedure:
A solution of 3.2 g. of methyl 3-[2-(1-naphthyloxy)ethylamino]benzoate and 1.68 g. of potassium hydroxide in 40 ml. of 95% ethanol is heated to reflux for 4 hours. After cooling and diluting with 80 ml. of water, the solution is acidified with concentrated HCl and filtered. Recrystallization from acetonitrile affords the white desired product, m.p. 150°-152° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1CCOCC1.CN>C1COCC1.C(Cl)Cl>[Cl:34][C:30]1[C:29]([F:35])=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][C@@H:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([C:36]([NH:40][CH3:39])=[O:38])[CH2:10]4)[CH:16]=3)[N:21]=[CH:20][N:19]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: CN1CCOCC1
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 108.2 %

Procedure:
A stirred solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (5.35 g, 9.80 mmol) in THF (50 ml) was cooled to −15° C. (acetone/ice). NMM (1.49 ml, 14.9 mmol) was added to the solution followed by IBCF (2.0 ml, 12.75 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with a 2.0M solution of methylamine in THF (10 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2×20 ml) and concentrated to give tert-butyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (5.94 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 560.1.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[CH3:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: Cc1ccccc1C(=O)c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1ccccc1/C(N)=C1\Sc2ccccc2C1=O
Yield: 50 %

Procedure:
Prepared as in Example 1 from 2-(2-methylbenzoyl)-benzo-[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 50% of theory.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]([NH:6][C@H:7]([C:21](O)=[O:22])[CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)=[O:5].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.C([O-])(=O)C.[Na+]>C(OCC)C.C(O)(=O)C.O1CCOCC1>[OH:22][C:21]1[N+:2]([O-:1])=[C:3]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:4](=[O:5])[NH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: COc1cc(C[C@H](NC(=O)C(CC(C)C)=NO)C(=O)O)cc(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)[O-]
Agent: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc(Cc2[nH]c(=O)c(CC(C)C)[n+]([O-])c2O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a dioxane solution (200 ml) containing 18.71 of N-(2-hydroxyimino-4-methylpentanoyl)-(3,4,5-trimethoxy)phenylalanine and 6.04 g of N-hydroxysuccinimide, was added 18.83 g of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 12 hours. After the reaction mixture was filtered, to the filtrate thus obtained was added 4.31 g of sodium acetate, then this mixture was stirred at room temperature for 5 hours. Then the reaction mixture was transferred to 600 ml of ice-water containing 5 ml of acetic acid, the precipitated semi-solid was collected and was dissolved in dichloromethane, the insoluble matters were removed by filtration, the organic layer was washed with in aqueous solution saturated with sodium chloride, then dried with magnesium sulfate. The solvent was removed by distillation to obtain yellow semi-solid, then 30 ml of diethyl ether was added and the mixture was allowed to stand for 2 days in a refrigerator to crystallize. The solid matter was collected by filtration and washed with diethyl ether to obtain 6.11 g of 5-hydroxy-3-isobutyl- 6-(3,4,5-trimethoxybenzyl)-1,2-dihydropyrazin-2-one 4-oxide as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].ClC1C=CC([N+]([O-])=O)=CC=1C=O.[BH4-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Preparation of 2-chloro-5-nitrobenzoyl alcohol 30 g of 2-chloro-5-nitrobenzaldehyde was dissolved in 500 mL of methanol and cooled to 0° C. A solution of 10 g of sodium borohydride in 100 mL of water was then added dropwise over 90 minutes while maintaining the temperature below 10° C. The resultant reaction mixture was then stirred for one hour, then acidified with 2N HCl and left stirring overnight. The solids were then, washed with water and dried, to produce 27 g of 2-chloro-5-nitrobenzyl alcohol as a white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([O:21][P:22]([O:32][CH2:33][CH2:34][OH:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:35][CH2:34][CH2:33][O:32][P:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=P(OCCO)(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
4-Nitrophenyl chloroformate (1.01 g; 5.04 mmol) was added at 0° C. under argon atmosphere to a solution of 2-[di(benzyloxy)phosphoryloxy]ethanol (1.62 g; 5.09 mmol) and triethylamine (0.7 ml; 5 mmol) in dichloromethane (20 ml). The mixture was stirred at ambient temperature for 30 minutes, evaporated and purified by flash chromatography, eluting with petroleum ether/ethyl acetate (40/60) to give 2-[di(benzyloxy)phosphoryloxy]ethyl 4-nitrophenyl carbonate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[CH2:16][CH2:15][CH:14]([NH:18][S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:21])=[O:20])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1.C(S(Cl)(=O)=O)CC>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[CH2:16][CH2:15][CH:14]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21)C1CC1
Agent: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 5 %

Procedure:
In analogy to the procedure described for the preparation of (rac)-cyclopropanesulfonic acid [4-(4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-amide (example 94), replacing cyclopropanesulfonyl chloride with propane-1-sulfonyl chloride. The title compound was obtained as a light brown oil in 5% yield. MS: 385.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([NH2:15])=[O:14])=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[C:5]([C:13]([NH2:15])=[O:14])=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1
Reactant: NC(=O)c1cc2scnc2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cc2scnc2cc1N

Procedure:
A solution of 5-nitrobenzothiazole-6-carboxamide (0.30 g, 1.34 mmol) in MeOH/EtOAc (1:1, 25 mL) is hydrogenated over 5% Pd/C at 60 psi for 1 h to give 5-aminobenzothiazole-6-carboxamide. This is immediately dissolved in triethyl orthoformate (30 mL) and the mixture is heated under gentle reflux for 18 h. An equal volume of petroleum ether is added to the cooled solution, precipitating thiazolo[5,4-g]quinazol-4(3H)-one (0.17 g, 57%) as a tan powder. 1H NMR (DMSO) δ12.30 (1H, brs), 9.67 (1H, s). 9.00 (1H, s), 8.31 (1H, s), 8.14 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[C:11]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:10][N:9]=[C:8]3[C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:7]=[N:6][CH:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.2 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-8-phenyl-N-(pyridin-2-ylmethyl) phthalazin-1-amine (50.0 mg, 0.124 mmol) in dichloromethane (5 mL) at ambient temperature was added pyridine (0.0200 mL, 0.247 mmol) followed by acetyl chloride (0.0132 mL, 0.185 mmol). After stirring for 5 h at room temperature, the reaction mixture was diluted with dichloromethane (50 mL) and the organic portion washed with water (10 mL) followed by brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 31 as described in general methods) to obtain N-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridin-3-yl)acetamide (25.0 mg, 45.3%) as a white solid. LCMS (Condition 4): retention time 2.08 min, [M+1]=447.2. HPLC (Condition 28): retention time=5.63 min, purity 94.65%. 1H NMR (400 MHz, CD3OD) δ 2.21 (s, 3 H), 4.65 (s, 2 H), 7.21-7.26 (m, 2 H), 7.49 (br s, 5 H), 7.69-7.73 (m, 2 H), 7.88-7.94 (m, 2 H), 8.28-8.30 (m, 1 H), 8.42 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 8.55 (d, J=2.0 Hz, 1 H), 8.90 (d, J=2.4 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[C:13]([N:15]([CH3:30])[C:16](=[O:29])[C:17]=1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[NH:20][CH:19]=1)=[O:14]>CN(C=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH:17]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[NH:20][CH:19]=2)[C:16](=[O:29])[N:15]([CH3:30])[C:13]1=[O:14]
Reactant: COc1ccc2[nH]cc(C3=C(c4c[nH]c5ccc(OC)cc45)C(=O)N(C)C3=O)c2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(C3C(=O)N(C)C(=O)C3c3c[nH]c4ccc(OC)cc34)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.8 %

Procedure:
To a solution of 2,3-bis(5-methoxy-1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.25 mmol) in DMF (5 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 3,4-bis(5-methoxy-1H-indol-3-yl)-1-methyl-2,5-dioxopyrrolidine (20 mg, 19.9%) as a mixture of two isomers (A:B=2:1) as pale red solids.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=2)[CH:4]=1.[CH3:24][Mg]Br>O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:11]=[C:10]([CH:12]([OH:13])[CH3:24])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[N:8]=2)[CH:4]=1
Reactant: C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1cc2cc(C(F)(F)F)cc(C=O)c2n1
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C

Procedure:
To a solution of 5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (0.5 g, 1.45 mmol) in tetrahydrofuran (10 mL) at −78° C. was added methyl magnesiumbromide (3 M in diethyl ether, 0.97 mL, 2.90 mmol). The reaction was allowed to gradually warm in the ice bath (ca. 1 h) to 0° C. The reaction which had been a suspension became a solution. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 444 mg (85%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.23 (s, 1H), 7.93 (s, 1H), 7.39 (s, 1H), 5.73 (s, 2H), 5.38 (q, J=6.4 Hz, 1H), 3.65 (m, 2H), 3.52 (bs, 1H), 1.71 (d, J=6.7 Hz, 3H), 0.94 (m, 2H), −0.03 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 147.3, 136.6, 128.0, 124.8, 124.7 (q, J=273 Hz), 124.7 (q, J=32 Hz), 121.3, 118.4 (q, J=4.8 Hz), 117.4 (q, J=2.9 Hz), 82.1, 68.2, 68.0, 23.4, 17.9, −1.4.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]1[CH:40]=[CH:39][C:17]([O:18][C:19]2[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][NH:35]3)=[CH:32][C:22]3[NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:25][C:21]=3[CH:20]=2)=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:19]2[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][N:35]3[S:9]([CH3:8])(=[O:11])=[O:10])=[CH:32][C:22]3[NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:25][C:21]=3[CH:20]=2)=[CH:39][CH:40]=1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.01 ml of triethylamine and 0.005 ml of methanesulfonyl chloride were added in order to an ethyl acetate (1 ml) solution of 20 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[C:17](=[S:22])([O:19][CH2:20][CH3:21])[S-:18].[K+]>O.Cl>[CH2:20]([O:19][C:17]([S:22][C:3]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:2]=1[F:1])=[S:18])[CH3:21]
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=S)Sc1cc(C(F)(F)F)ccc1F
Temperature: -59 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
2-Fluoro-5-trifluoromethylaniline (14 g) was suspended in 30 ml of water and 10 ml of concentrated hydrochloric acid. The suspension was cooled to −5° C. while a solution of 5.93 g of sodium nitrite in 30 ml of water was added dropwise, followed by stirring at −59° C. for 2 hours. Then the solution was added to a solution of 16 g of potassium O-ethyl dithiocarbonate in 20 ml of water (40 to 50° C.), followed by stirring for 1 hour. The reaction mixture was extracted with an aqueous solution of ethyl acetate, dried and concentrated, giving 22 g of 3-ethoxythiocarbonylthio-4-fluorobenzotrifluoride.