Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][C:6]=1[F:28].[OH-].[K+]>CO.O1CCCC1>[F:28][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:26])[CH3:27])[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:29])=[O:2]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)cc(O)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.3 %

Procedure:
A solution of [2-fluoro-4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-acetic acid methyl ester (Intermediate 21, 0.037 g, 0.0493 mmol) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with a 2M solution of potassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.024 g, 69%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[CH:3]=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]1[CH2:25][O:24][CH:23]=[CH:22][CH2:21]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:24]1[CH2:25][CH2:20][CH2:21][CH2:22][CH:23]1[N:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[CH:3]=[N:2]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnn(C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
To a suspension of 1H-pyrazole-4-carboxylic acid (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50° C. to give 61.2 g of a white powder (yield: 70%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Cc1cccc(-c2cc3cnc(N)nc3nc2N)c1C
Reactant: CC(C)(C)N=C=O
Product: Cc1cccc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1C

Procedure:
The title compound was prepared from 0.5007 g of 6-(2,3-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 92 and 0.23 mL tert-butyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (2:1) to CHCl3 :EtOAc (1:1); mp 326°-330° C., MS(CI).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=4)=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=463.6 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-(trifluoromethyl)phenyl isocyanate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][O:22]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]>O1CCCC1>[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC(O)CN1CCOCC1
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1 ml) and morpholine (0.1 ml) to N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea (100 mg), the mixture was heated at 50° C. for 30 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (32 mg) as light yellow crystals.
Reaction SMILES: C([O:3][C:4]1(OCC)[CH2:11][C:10]2[C:5]1=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)C.Cl.O>C1COCC1.O>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:14][CH3:15])[C:4](=[O:3])[CH2:11]2
Reactant: CCOC1(OCC)Cc2cc(OC)c(OC)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
7,7-Diethoxy-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene (1.76 g, 6.98 mmol) is stirred in a mixture of THF/water (6/1) at ambient temperature. 815 mg of an aqueous 11N HCl solution (1.1 eq, 7.7 mmol) are then added. The reaction mixture is stirred for 2 hours ambient temperature. Water is added to facilitate two extractions with ethyl acetate (2×30 mL). The organic phases are dried over MgSO4 and then subjected to drying. There are obtained 1.01 g of the title product in the form of a grey powder.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:28]1C=C(C=C[CH:35]=1)C#N>>[F:25][C:2]([F:1])([F:26])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[CH:35][CH:28]=[C:22]([C:21]#[N:20])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Product: Cc1ccc(Nc2cccc(C#N)c2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) in accordance with the general method of example 20 using 3-Bromobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a light brown solid, MS (ISP): m/e=404.0 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[N:11]=[N:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccncc2)n[nH]1
Product: Clc1ccc(-c2ccncc2)nn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
75.6 g 6-Pyridin-4-yl-2H-pyridazin-3-one is added in small portions to 234.5 g phosphorus oxychloride and the resulting mixture is stirred for 1 h at 100° C. Diluting into ice cold water, adjusting the pH 7 with aqueous sodium hydroxide and extraction with dichloromethane yielded 54 g 3-Chloro-6-pyridin-4-yl-pyridazine which is used without further purification.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([NH:44][C:45]2[C:50]([NH2:51])=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:57])=[O:56])[CH:53]=[CH:54][C:46]=23)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH2:40][CH:41]([NH:44][C:45]2[C:50]([NH:51][C:7](=[O:9])[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:49][N:48]=[C:47]3[N:52]([S:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)(=[O:56])=[O:57])[CH:53]=[CH:54][C:46]=23)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)CC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 45.1 %

Procedure:
Cyclopentylacetic acid (0.532 ml, 4.24 mmol), diisopropylethylamine (1.5 ml, 8.50 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.89 g, 4.70 mmol) were added sequentially to a solution of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 4.00 mmol) in CH2Cl2 (60 ml) at 25° C. The reaction mixture was stirred for 9 h at 25° C., then was partitioned between 1.0 M HCl (125 ml) and CH2Cl2 (125 ml). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 40%) as an off-white solid. LCMS (Method G, ESI): RT=1.15 min, m+H=582.5. This material was used in the next step below without additional characterization.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:10])[CH2:5][C:6]=1[C:7]([NH2:9])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4](=[O:10])[CH2:5][C:6]=1[C:7]#[N:9]
Reactant: CC1=C(C(N)=O)CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=C(C#N)CC(=O)N1

Procedure:
A mixture of 0.9 g (4.6 mmol) of 2-methyl-5-oxo-4,5-dihydropyrrole-3-carboxamide, 1.4 g (9.2 mmol) of phosphorus oxychloride and 0.9 g (6.4 mmol) of potassium carbonate in 50 ml of acetone was refluxed for 6 h. The mixture was then concentrated and the resulting residue was chromatographed over silica gel (mobile phase: cyclohexane:ethyl acetate 10:1 to 1:1). This gave 0.15 g (19% of theory) of the desired product (IR: 2220 cm−1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[CH:9]2[CH2:30][CH:6]1[CH:7]=[CH:8]2)=[O:4]>C(O)C.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:11]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH3:12])[CH:9]2[CH2:30][CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1C2C=CC(C2)C1N(C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)C1C2CCC(C2)C1N(C)S(=O)(=O)c1ccc(O)cc1
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of 3-[(4-benzyloxy-benzenesulfonyl)-methyl-amino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (1.5 g, 3.51 mmol) in ethanol-CH2Cl2 (45 mL-5 mL) were added 10% Pd—C (1.12 g, 1.05 mmol) and 1,4-cycloexadiene (3.32 mL, 35.1 mmol) at room temperature. The mixture was stirred for 12 h and then filtered through celite. The organic solution was concentrated and the residue was purified by flash chromatography eluting with 40% ethyl acetate/hexanes to give 3-[(4-hydroxy-benzenesulfonyl)-methyl-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (97% yield). Mp=163-164° C. (white solid).
Reaction SMILES: [CH:1]1([C:7]([O:9]C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][NH2:12].O>C(O)(C)C>[CH:1]1([C:7]([NH:11][NH2:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)C1CCCCC1
Solvent: O
Solvent: CC(C)O
Product: NNC(=O)C1CCCCC1

Procedure:
28 Grams of methyl cyclohexylcarboxylate and 15 g of 85%--NH2NH2.H2O were dissolved in 50 ml of isopropyl alcohol, and the solution was refluxed by heating for 10 hours. The reaction mixture was concentrated, and the crystals precipitated by adding water were collected by filtration, then the crystals were washed with water, then recrystallized from water to yield 20 g of cyclohexane-carbohydrazide in the form of colorless needle-like crystals. Melting point: 155.5°-156.5° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2C1
Yield: 65 %

Procedure:
In analogy to Example 22A, the title compound was prepared from ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (100 mg, 0.35 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline from Example 4A (93 mg, 0.37 mmol) to give 157 mg (72% purity, 65% yield), which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:28])[N:7]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C@H:14]([OH:27])[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH3:8])([CH3:4])[CH3:3].CN(C1C=CC=CN=1)C.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39].CC=C(C)C>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6](=[O:28])[N:7]([CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][C@@H:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[O:27][C:38]1=[O:39])[CH3:8])([CH3:1])[CH3:3]
Reactant: COc1ccc2nccc([C@@H](O)CNCCCN(C)C(=O)OC(C)(C)C)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC=C(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H]3CN(CCCN(C)C(=O)OC(C)(C)C)C(=O)O3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.3 %

Procedure:
A mixture of {3-[(R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethylamino]-propyl}-methyl-carbamic acid dimethyl-ethyl ester (830 mg, 2.1 mmol), 4 (dimethylamino)pyridine (DMAP) (329 mg, 2.66 mmol), 1,1′-carbonyldiimidazole (CDI) (454 mg, 2.77 mmol) and methylene chloride stabilized over amylene (20 ml) was stirred under argon, at room temperature, for 4 days. The solution was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (95-5) to give {3-[(R)-5-(6-methoxy-quinolin-4-yl)-2-oxo-oxazolidin-3-yl]-propyl}-methyl-carbamic acid dimethyl-ethyl ester (770 mg, 88%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:27]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:15]3[CH:7]=[C:8]([CH3:27])[S:9][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2ncnc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl
Reactant: c1c[nH]cn1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 5-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH:15]=O)=[C:11]([CH3:17])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:19][C:20]1[C:21]([OH:35])=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1.C([O-])(=O)C.[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[CH:15][NH:19][C:20]3[C:21]([OH:35])=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[C:11]([CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2[nH]c(C)c(C=O)c2=O)cc1C
Reactant: Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=CNc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 1-(3,4-dimethylphenyl)-3-methyl-5-oxo-3-pyrazolin-4-carbaldehyde (10 mg, 0.043 mmol) and 3′-amino-2′-hydroxybiphenyl-3-carboxylic acid hydrochloride (11 mg, 0.042 mmol) in ethanol (1 mL) was shaken with 0.2M aq. sodium acetate (0.25 mL, 0.05 mmol) for 1 h. 0.06M aq. hydrochloric acid (3 mL) was added and shaking continued for 1 h. The solid was filtered, washed with water and dried under reduced pressure to afford the title compound (14 mg, 74%) as a cream-coloured powder. 1H NMR (300 MHz, d6-DMSO) δ 13.08 (br s, 1H), 11.79 (d, J=13.8 Hz, 1H), 9.56 (s, 1H), 8.71 (d, J=13.2 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.83-7.80 (m, 3H), 7.71 (d, J=8.2 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.16-7.11 (m, 3H), 2.31 (s, 3H), 2.26 (s,3H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2](=[C:16]([F:18])[F:17])[CH2:3][CH2:4][S:5]([C:7]1[S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]=1)=[O:6].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[F:1][C:2](=[C:16]([F:17])[F:18])[CH2:3][CH2:4][S:5]([C:7]1[S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]=1)(=[O:27])=[O:6]
Reactant: O=S(CCC(F)=C(F)F)c1nc2cnccc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(=O)(CCC(F)=C(F)F)c1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
2-(3,4,4-trifluoro-but-3-enylsulfinyl)-thiazolo[4,5-c]pyridine (0.1 g) was dissolved in methylene chloride (5 ml), m-chloroperbenzoic acid (0.07 g) was added and the mixture was stirred at room temperature for 2 hours. The mixture was washed with 1% aqueous sodium metabisulfite, aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel using methylene chloride:ethyl acetate (85:15) to give the product as a brown semi-solid (0.05 g).
Reaction SMILES: CC([S@]([NH:7][C@H:8]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)C>C(Cl)Cl.O1CCOCC1.Cl>[F:21][C:20]([F:22])([F:23])[CH2:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:7]
Reactant: CC(C)(C)[S@@](=O)N[C@@H]1CCCc2c(OCC(F)(F)F)cccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H]1CCCc2c(OCC(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of Intermediate 14A (206 mg, 0.590 mmol) in DCM (1 mL) was added 4 N HCl (147 μl, 0.590 mmol) in dioxane. The resulting mixture was stirred at rt for 0.5 h. The solvents were evaporated and DCM (3×) was added and evaporated. The resulting white solid was vacuum dried for 1 h to give Intermediate 14 (0.13 mg, 0.51 mmol, 86% yield) in HCl salt which was used directly without further purification. LCMS=1.55 min [M+1-17]=229 (Method B).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]2[C:9]=1[CH2:10][CH:11]([NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2>O1CCCC1>[CH2:21]([NH:20][CH:11]1[CH2:12][C:13]2[C:9](=[C:8]([CH3:7])[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]=2[CH3:19])[CH2:10]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(C)c(C)c2c(c1C)CC(NC(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C)c(C)c2c(c1C)CC(NCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 20 h

Procedure:
1M Lithium aluminium hydride (2.4 ml) in tetrahydrofuran is added dropwise to a solution of N-(4,5,6,7-tetramethyl-indan-2-yl)-benzamide (352 mg) in anhydrous THF (10 ml) under nitrogen at room temperature. The reaction mixture is allowed to stir at 50° C. for 20 hours. After 4 hours more 1M Lithium aluminium hydride (1.2 ml, 1.20 mmole) in THF is added. On cooling the reaction mixture is quenched with ice water. The aqueous phase is washed with diethyl ether (×3) and the organic layers combined, treated with magnesium sulphate, filtered and the solvent removed in vacuo.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2.CN([CH:20]=[O:21])C>>[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:20]=[O:21]
Reactant: Clc1cc(Br)c2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(Br)cc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Phosphorus oxychloride (3.11 mL, 33.4 mmol) was added dropwise to a 0° C sample of DMF (30 mL). The reaction was stirred 30 min at 0° C., then 7-bromo-5-chloro-1H-indole (7.0 g, 30.4 mmol) in DMF (5 mL)was added and the reaction was warmed to ambient temperature and stirred 20 hours. Ice water (300 mL) was added, and the resulting thick solid was filtered. The product was detected by TLC in both filtrate and cake. Cake and filtrate were combined, and sodium hydroxide (10N) was added until most solids disappeared, then the mixture was extracted with ethyl acetate (4×100 mL). The organic layers were dried with MgSO4 and evaporated to a solid that weighed 10.5 g. The residue was dissolved in 400 mL boiling ethyl acetate, the insoluble material was filtered away and the filtrate was evaporated. 7-bromo-5-chloro-1H-indole-3-carbaldehyde (6.45 g, 24.95 mmol, 82% yield) was obtained as an off-white solid. 1H-NMR (CDCl3, 400 MHz) δ 9.99 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.47 (d, J=2.0 Hz, 1H). LC/MS (HPLC method 4): tR=2.87 min, 257.91(MH)+.
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:9][O:8][CH2:7][CH2:6][NH:5]1)[CH3:3].[Cl:10][CH2:11][C:12]#[C:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][CH2:11][C:12]#[C:13][CH2:14][N:5]1[CH2:6][CH2:7][O:8][CH2:9][C@H:4]1[CH2:2][CH3:3]
Reactant: ClCC#CCCl
Reactant: CC[C@@H]1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H]1COCCN1CC#CCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R)-3-ethylmorpholine hydrochloride (0.2 g), 1,4-dichloro-2-butyne (0.5 ml) and potassium carbonate (0.71 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 hours. After removal of the solvent, ethyl acetate and sodium hydrogen carbonate solution were added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:1) as an eluent to give (3R)-4-(4-chloro-2-butynyl)-3-ethylmorpholine (0.2 g) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:26])[CH2:8][C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.[ClH:27]>ClCCl.CCOCC>[ClH:27].[N:4]1([C:7](=[O:26])[CH2:8][C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][NH:10]2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CC(=O)N1CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(C[C@@H]1Cc2ccccc2CN1)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2.88 g (7.18 mmol) of the compound obtained in Step A in 16 mL of dichloromethane, there are added dropwise 80 mL (80 mmol) of 1M solution of HCl in ether. The batch is stirred at ambient temperature for 15 hours, and then the suspension is filtered and the precipitate washed with ether. After drying, the title product is obtained in the form of a solid.