Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:37]([C:36]1[C:32]([O:31][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=2)=[N:33][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=1)=[O:38]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of ethyl (3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (7.20 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (3.01 g), potassium carbonate (2.21 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (6.84 g, yield 73%) from a fraction eluted with ethyl acetate-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 145-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[NH:9]2)[C:3]=1[CH3:19].C(=O)(OC(C)(C)C)[O:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[C:3]=1[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1c(Br)ccnc1C1CC[C@]2(CCN(C)C2=O)N1
Solvent: ClCCl
Product: Cc1c(Br)ccnc1[C@H]1CC[C@]2(CCN(C)C2=O)N1C(=O)OC(C)(C)C
Yield: 62.4 %

Procedure:
To a solution of (5R)-2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 10) (554.4 mg, 0.8500 mmol) in DCM (2 mL) was added and tert-butoxycarbonyl tert-butyl carbonate (373.2 mg, 1.71 mmol) the reaction was then stirred at room temperature for 3 days. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc in isohexane from 0% to 100%. A slower running material was isolated tert-butyl (2R,5R)-2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D98) (225.1 mg, 0.5305 mmol, 62% yield) as a colourless oil; M/Z: 423.8, 425.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5][C:4]=2[N:3]=1.C(C1C(O)=CC=C2C=1OC(=O)C([C:28]1[CH:44]=[CH:43][C:31]([C:32]([NH:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41]OC[CH2:38]3)=[O:33])=[CH:30][CH:29]=1)=C2C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)C.O>[OH:14][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([N:34]4[CH2:35][CH2:36][N:37]([CH3:38])[CH2:42][CH2:41]4)=[O:33])=[CH:43][CH:44]=3)[CH:11]=[CH:10][C:9]=2[C:8]=1[CH:12]=[O:13]
Reactant: O=Cc1c(O)ccc2nc(Cl)ccc12
Reactant: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2c(C=O)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(C(=O)c2ccc(-c3ccc4c(C=O)c(O)ccc4n3)cc2)CC1

Procedure:
A mixture of 2-chloro-6-hydroxyquinolin-5-carbaldehyde (3) (104 mg, 0.5 mmol), 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (4) (198 mg, 0.7 mmol) and K2CO3 (174 mg, 1.25 mmol) in a mixture of i-PrOH and water (6 mL 10:1) was purged with Argon for five minutes in a microwave vessel. A tablet of PdOAc2(Sphos)4 (Aldrich, Cat. No. 694088) was added under an Argon atmosphere then the vessel was sealed and irradiated for 45 min at 165° C. Upon cooling, the reaction mixture was filtered through a silica plug using MeOH. The solution was evaporated and purified by Flash chromatography using 0-5% MeOH in CH2Cl2. The product was recrystallized from CH2Cl2/hexanes to afford the title compound. MS (ESI): 376 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 10.74 (s, 1H), 9.44 8.25, 7.21 and 7.49 (4d, 4×1H), 8.29 and 7.54 (2d, 2×2H), 3.64, 3.38, 2.41 and 2.33 (4 broad s, 4×2H), 2.23 (s, 3H).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][NH:16]C(=O)C)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.O.[OH-].[K+].Cl>C(O)CO>[NH2:16][CH2:15][CH2:14][N:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: NCCn1ccc2c1-c1ccccc1CC2
Temperature: 120 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
N-[2-(4,5-Dihydro-1H-benzo[g]indol-1-yl)ethyl]acetamide (5.0 g) was suspended in 60 ml of ethylene glycol and 25 ml of water under argon and treated with 5.0 g of powdered potassium hydroxide. The mixture was stirred at 120° C. for 18 hours, subsequently cooled and treated with 150 ml of 2N hydrochloric acid while cooling. The solution was washed with 200 ml of methylene chloride, the organic phase was extracted three times with 100 ml of 2N hydrochloric acid each time, the aqueous phases were combined and made strongly alkaline with 28% sodium hydroxide solution while cooling with ice. The aqueous solution was extracted once with 200 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 4.0 g of brown oil, was chromatographed on 250 g of silica gel with methylene chloride/methanol mixtures (99:1 to 19:1) as the eluent. There were obtained 3.7 g (88%) of 1-(2-aminoethyl)-4,5-dihydro-1H-benzo[g]indole which was processed without further purification.
Reaction SMILES: COC(=O)C[NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](N)=[CH:44][CH:43]=1>CCCCCCC.C(OCC)(=O)C>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[CH:44][CH:43]=1
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 4-amino-benzoic acid methyl ester (commercially available, CAS RN 619-45-4) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light brown foam (29%). MS (ESI): m/z=617.136 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([S:17](Cl)(=[O:19])=[O:18])=[CH:6]1)(=[O:3])[NH2:2].[OH-].[NH4+:22]>C(Cl)Cl>[N+:14]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH:6]=[C:7]2[S:17](=[O:19])(=[O:18])[NH2:22])([O-:16])=[O:15]
Reactant: [NH4+]
Reactant: NC(=O)Cn1cc(S(=O)(=O)Cl)c2cc([N+](=O)[O-])ccc21
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)Cn1cc(S(N)(=O)=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
The 1-carbamoylmethyl-5-nitro-1H-indole-3-sulfonyl chloride (0.37 g, 1.165 mmole) of Step 2 was suspended in methylene chloride (2 ml) and added to ammonium hydroxide (4 ml) at room temperature. After stirring for 2 h at room temperature, the reaction flask was heated on a steam bath for 35 min and then allowed to cool to room temperature. The yellow solid which precipitated was filtered off and dried to afford 0.24 g (0.81 mmole, 69% yield) of 2-(5-nitro-3-sulfamoyl-indol-1-yl)-acetamide. Step 4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][N:15]=[C:16]=[S:17]>ClCCl>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:16]([NH:15][CH3:14])=[S:17]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 2-aminobiphenyl (6.3 g), methylisothiocyanate (3.8 g) and dichloromethane (45 ml) was stirred at ambient temperature for four days to give N-(2-biphenylyl)-N'-methylthiourea (m.p. 152°-153° C.).
Reaction SMILES: [CH:1]1[C:10]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:9][C:8]2[C:3](=[C:4]([S:16]([OH:19])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=2[NH2:15])[CH:2]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:15][C:7]1[C:8]2[C:3](=[CH:2][CH:1]=[C:10]([S:11]([O-:14])(=[O:13])=[O:12])[CH:9]=2)[C:4]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:5][CH:6]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccc(S(=O)(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc12

Procedure:
A 50.0 g amount of (61.5%) 1-naphthylamine-4,7-disulfonic acid is dissolved in 150 ml of water and 5N sodium hydroxide is added until basic pH (10-11). The solution is warmed and ethyl alcohol is added until a precipitate forms. The solid is collected by filtration, washed with 85% ethyl alcohol, ethyl alcohol and ether and is dried in vacuo at 110° C. to give 31.0 g of 4-amino-1,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.Cl.[C:12]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[NH2:19])([CH3:15])([CH3:14])[CH3:13].CCN(C1C=CC=CC=1)CC>C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][CH:3]=2)[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1ccnc2ccnn12
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1cc(Nc2ccnc3ccnn23)cc(C(C)(C)C)c1O
Temperature: 120 °C
Yield: 40.4 %

Procedure:
A suspension of 7-chloropyrazolo[1,5-a]pyrimidine (1.0 g), 3,5-di-t-butyl-4-hydroxyaniline hydrochloride (1.8 g) and diethylaniline (2.3 ml) in toluene (50 ml) is heated at 120° C. for 30 minutes. After cooling, the solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent; CHCl3) to give 7-(3,5-di-t-butyl-4-hydroxyphenyl)aminopyrazolo[1,5-a]pyrimidine (890 mg) as colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([NH:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2nc3ccccc3nc12
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2nc3ccccc3nc12

Procedure:
Scheme 8 provides a synthetic route to a 1-acetamido-N-ethyl phenazine derivative (35). A 3-amino-catechol hydrochloride (30) is reacted with silver oxide and anhydrous sodium sulfate in ethyl acetate to give 3-amino-1,2-quinone (31), which is further reacted in situ with ortho phenylenediamine (32) to give 1-amino phenazine (33). The amino phenazine (33) is acetylated with acetic anhydride in acetic acid to give 1-acetamido phenazine (34). The resulting 1-acetamido phenazine is reacted with diethyl sulfate in the presence of potassium carbonate to give N-ethyl-1-acetamido-phenazine (35).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([O:23][C:24]([C:26]1[CH:27]=[C:28]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](O)=[O:38])[CH:29]=[CH:30][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](=[O:38])[NH:18][C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C:10]3[O:11][C:7]([C:2](=[O:6])[CH3:1])=[CH:8][CH:9]=3)[N:14]=2)[CH:27]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)(C)OC(=O)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C(=O)OC(C)(C)C)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-tert-butoxycarbonyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.09 min; [M+H]+=477.45.
Reaction SMILES: [C:1](OCC)(=[O:5])[C@H:2]([CH3:4])[OH:3].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[OH:3][C@@H:2]([CH3:4])[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5]
Reactant: CCOC(=O)[C@H](C)O
Reactant: C1COCCN1
Product: C[C@H](O)C(=O)N1CCOCC1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH:8]=[O:9]
Reactant: Clc1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 150 °C

Procedure:
To acetonitrile (15.0 mL) were added 3-chloro-4-hydroxy-benzaldehyde (556, 0.6 g, 4 mmol), 4-chlorobenzyl bromide (557, 1.2 g, 6 mmol), and potassium carbonate (0.9 g, 7 mmol). The reaction was heated to 150° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate: hexanes) (558, 0.85 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][N:24]=[CH:10]2
Reactant: Cc1cc(C#N)cc(Cl)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-chloro-5-methylbenzonitrile (3.00 g, 18.0 mmol) in CHCl3 (50 mL) was added acetic anhydride (3.9 mL, 41.4 mmol). The mixture was stirred at room temperature overnight and then heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and potassium acetate (530 mg, 5.40 mmol) and isoamyl nitrite (5.28 mL, 39.6 mmol) were added. The mixture was heated at reflux for 3 days. The reaction mixture was washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. To this was added methanol followed by water (25 mL) and 38% HCl (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the pH was adjusted to about 7. The solids were isolated by filtration and then washed with water (2×30 mL) and heptane (2×30 mL). Purify by Biotage chromatography (CH2Cl2-heptane (1:1)/MeOH gradient to afford 7-chloro-1H-indazole-5-carbonitrile was isolated as a white solid (585 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and m-anisidine, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 3.72 (s, 3H), 6.74 (m, 1H), 7.09 (m, 1H), 7.26 (br m, 2H), 7.40 (br s, 1H), 7.47 (m, 1H), 7.88 (m, 1H), 10.34 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
6.0 G. of 1-acetamido-2-nitro-4-phenoxybenzene and 20 ml. sodium hydroxide in methanol is warmed gently until homogeneous, diluted with water and ice, and the methanol evaporated to give 1-amino-2-nitro-4-phenoxybenzene.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)c2ccc(O)c(Cl)c2Cl)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=NO)c2ccc(O)c(Cl)c2Cl)cc1

Procedure:
A mixture of 2,3-dichloro-4-hydroxy-4'-methylbenzophenone and 12.5 g of hydroxylamine hydrochloride in 200 ml of pyridine is refluxed for 2 hours. Thereafter the pyridine is evaporated off under vacuum and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. The ethyl acetate extract is, successively, washed with water, dried and concentrated to dryness leaving 2,3-dichloro-4-hydroxy-4'-methylbenzophenone oxime.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:12](#[N:15])[CH:13]=[CH2:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1>[C:12]([CH2:13][CH2:14][N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)#[N:15]
Reactant: C=CC#N
Reactant: c1c[nH]c(Cn2ccnc2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#CCCn1cccc1Cn1ccnc1
Reaction time: 18 h

Procedure:
2-(Imidazol-1-ylmethyl)pyrrole (4.41 g) and acrylonitrile (6.0 ml) were dissolved in dioxan (75 ml) and benzyltrimethylammonium hydroxide (1.5 ml of 40% solution in methanol) was added. The mixture was warmed to 55° for 1 hour and then allowed to stand at room temperature for 18 hours. It was then poured into water and the mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform gave 1-(2-cyanoethyl)-2-(imidazol-1-ylmethyl)pyrrole (5.0 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([C:25]3[S:26][C:27]([F:30])=[CH:28][N:29]=3)CC3C=CC(OC)=CC=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:30][C:27]1[S:26][C:25]([NH:15][S:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=2[O:32][CH3:31])=[N:3][N:4]=[CH:5]3)(=[O:13])=[O:14])=[N:29][CH:28]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncc(F)s2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1nncc2cc(S(=O)(=O)Nc3ncc(F)s3)ccc12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
A vial was charged with 1-chloro-N-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)phthalazine-6-sulfonamide (Intermediate CCCC) (55.94 mg, 0.120 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, San Diego, Calif., 31.8 mg, 0.144 mmol), Pd(AmPhos)2Cl2 (4.26 mg, 6.02 μmol), potassium phosphate (77 mg, 0.361 mmol), 1,4-dioxane (451 μl), and water (150 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 30 min, the mixture was diluted with MeOH and concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 0 to 7% MeOH/DCM) to give N-(5-fluorothiazol-2-yl)-1-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine-6-sulfonamide (35.18 mg, 0.073 mmol, 60.4% yield) as a cream-colored solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.88 (s, 1H), 9.96 (s, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.22 (dd, J=1.9, 8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.60-7.52 (m, 2H), 7.41 (s, 1H), 3.77 (s, 3H); m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([N:48]=[C:49]=[O:50])[CH:45]=[CH:46][CH:47]=1>ClCCl>[Cl:41][C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:10]3[C:9]([CH2:8][O:7][C:6]4[CH:32]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[CH3:33])=[C:18]4[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]4[CH3:19])=[CH:12][CH:11]=3)=[C:24]([O:30][CH3:31])[CH:25]=2)=[O:50])[CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)Nc2cccc(Cl)c2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 20.3 mg, 0.0451 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), then triethylamine (13.6 μL, 0.0977 mmol) and 3-chlorophenyl isocyanate (6 μL, 0.05 mmol) were added to the mixture successively. After the reaction mixture was stirred for 1 hour at room temperature, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.4 mg) as a colorless solid. (Yield 82%)