Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:23][C:22](=[O:24])[O:21][N:20]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.Br[CH2:37][CH2:38][Cl:39].N12CCCN=C1CCCCC2>CN(C)C(=O)C>[Cl:39][CH2:38][CH2:37][N:23]1[C:22](=[O:24])[O:21][N:20]=[C:19]1[C:9]1[C:8]2[CH:25]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:26]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)[nH]3)c2cc1C1CC1)S(C)(=O)=O
Reactant: ClCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)n3CCCl)c2cc1C1CC1)S(C)(=O)=O
Yield: 30.3 %

Procedure:
A mixture of Example 10G (188 mg, 0.376 mmol), 1-bromo-2-chloroethane (0.033 mL, 0.395 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.062 mL, 0.414 mmol) in N,N-dimethylacetamide (6 mL) was heated in a sealed tube at 100° C. for 16 hours, cooled and concentrated. The residue was chromatographed on silica gel eluting with hexane to 3:1 hexane/ethyl acetate to give the title compound as a solid (64 mg, 30%). MS (ESI+) m/z 579 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[NH:13]1[CH:17]=[N:16][N:15]=[N:14]1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:14]1[N:15]=[N:16][CH:17]=[N:13]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: c1nnn[nH]1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cn1ncnn1)c1ccc(Cl)cc1Cl
Yield: 42.7 %

Procedure:
A solution of 15.9 g (71 mmol) of 2,2',4'-trichloroacetophenone in 100 ml of methylene chloride was slowly added dropwise while cooling with ice to a solution of 4.98 g (71 mmol) of tetrazole and 14.4 g (142 mmol) of triethylamine in 100 ml of methylene chloride and heated under reflux for 16 hours. The reaction mixture was added to 100 ml of water and extracted three times with 100 ml of methylene chloride each time. The combined organic phases were dried over magnesium sulphate and concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). There were obtained 4.75 g (26%) of 1-(2,4-dichloro)-2-tetrazol-1-yl-ethanone and 7.80 g (43%) of 1-(2,4-dichlorophenyl)-2-tetrazol-2-yl-ethanone.
Reaction SMILES: C[O:2][C:3]1[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[CH:6]1[C:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9][C:8]=2[C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1cccc2c1Sc1ccccc1CC2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cccc2c1Sc1ccccc1CC2
Temperature: 180 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
4-Methoxy-10,11-dihydro-dibenzo[b,f]thiepine (2.42 g, 10 mmol) and pyridine hydrochloride (15 g) were heated with stirring at 180° C. for one hour. Water (100 ml) was added to the reaction mixture and the organics were extracted with ethyl acetate (3×100 ml). The organics were combined and washed with 2N HCl (50 ml), brine (50 ml), and dried over magnesium sulphate. The solvent were removed in vacuo and the residue was purified by column chromatography (1:9; dichloromethane:hexane) to give the desired compound as a white solid (1.55 g, 68%). 1HNMR (300 MHz, DMSO-d6): δH=3.13–3.23 (4H, m), 6.70 (2H, t), 6.97–7.15 (4H, m), 7.38 (1H,s) 9.78 (1H, s); m/z (LC-MS, ESP), RT=4.59 min, (M++1)=229.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[C:11]([CH2:12][OH:13])=[C:10]([CH3:14])[O:9][N:8]=1)[CH2:4][CH2:5][CH3:6].[CH:15]([NH:18][C:19]([C:21]1[S:25][C:24](Cl)=[N:23][CH:22]=1)=[O:20])([CH3:17])[CH3:16].O>C1COCC1>[CH:15]([NH:18][C:19]([C:21]1[S:25][C:24]([O:13][CH2:12][C:11]2[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][O:9][C:10]=2[CH3:14])=[N:23][CH:22]=1)=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)NC(=O)c1cnc(Cl)s1
Reactant: CCCCc1noc(C)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1noc(C)c1COc1ncc(C(=O)NC(C)C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of NaH (55%, 58 mg, 2.4 mmol) in THF (3 mL) at 0° C., was added a solution of (3-butyl-5-methyl-isoxazol-4-yl)-methanol (169 mg, 1.0 mmol) in THF (3 mL) dropwise. The resulting mixture was stirred for 1 h and then cooled to 0° C. and then a solution of 2-chloro-thiazole-5-carboxylic acid isopropylamide (205 mg, 1.0 mmol) in THF (3 mL) added dropwise and the resulting mixture stirred at room temperature overnight. Water was then added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane, then 0 to 60% ethyl acetate in heptane) gave the title compound (145 mg, 43%) as a white solid. MS: m/e=338.4 [M+H]+.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccccc1I
Product: COc1ccccc1NC(=O)c1ccccc1
Yield: 20.7 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with 2-iodoanisole (135 μL, 1.04 mmol) at 40° C. for 18 h. The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 15 mL fractions). Fractions 8–12 provided 49 mg (21% yield) of the product as a colorless oil. The 1H NMR spectrum was in accord with that reported by Narasaka et al. Tsutsi, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 1869.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:13][N:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([C:30]2[CH:34]=[C:33]([CH:35]=O)[O:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[C:11]3[C:12]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][N:21]([CH2:35][C:33]5[O:32][N:31]=[C:30]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)[CH:34]=5)[CH2:20][CH2:19]4)=[N:13][N:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2noc3cnnc(OCC4CCNCC4)c23)cc1
Reactant: O=Cc1cc(-c2ccccc2)no1
Product: c1ccc(-c2cc(CN3CCC(COc4nncc5onc(-c6ccccc6)c45)CC3)on2)cc1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 89 instead of the compound obtained in Example 11 and the compound obtained in Example 7 instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:18])=[C:11]([F:10])[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(F)c(F)c1
Product: Fc1ccc(Nc2nc(Cl)ncc2F)cc1F

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoroaniline gave 2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.10 (d, 1H, J=2.1 Hz), 7.72 (m, 1H), 7.22 (m, 2H), 6.95 (bs, 1H); LCMS: purity: 93%; MS (m/e): 260 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.C1COCC1.[Li]CCCC>C1(C)C=CC=CC=1>[CH3:19][C:5]1[CH:4]=[CH:3][C:2]([B:24]([OH:25])[OH:23])=[CH:18][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)cc1Oc1ccc(C(F)(F)F)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(B(O)O)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: -40 °C
Reaction time: 1 h
Yield: 126.8 %

Procedure:
2-(5-Bromo-2-methylphenoxy)-5-(trifluoromethyl)pyridine (1 g, 0.003 mol) and triisopropylborate (0.8 mL, 0.003 mol) were dissolved in toluene (20 mL) and THF (5 mL) and cooled to −78° C. under a N2 atmosphere. n-BuLi (2.69 mL, 0.003 mol) was added while maintaining the reaction at −70° C. and then the reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20-0° C. and then the reaction was quenched with 2N HCl. The reaction mixture was warmed to RT, concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (1.13 g). m/z (296.4, 298.3, M− H−).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[O:9][C:10]([CH3:15])=[C:11]([CH2:13]Cl)[N:12]=1)([CH3:7])([CH3:6])[CH3:5]>CS(C)=O>[C:4]([C:8]1[O:9][C:10]([CH3:15])=[C:11]([CH2:13][C:1]#[N:2])[N:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1oc(C(C)(C)C)nc1CC#N
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To 5.72 g of NaCN (116.8 mmol), dissolved in 77 ml of DMSO, was slowly added via dropping funnel 14.14 g of the above prepared 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (75.3 mmol) at such a rate that the internal temperature stayed at 25–30°. Stirring was continued for an additional 1.5 h at 35°. The reaction mixture was then poured onto crashed ice/AcOEt, the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Thereby, 13.19 g of the title product was obtained, which was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=Cc1ccc(O)cc1Cl
Product: O=C(C=Cc1ccc(O)cc1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(2-Chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl) phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2-chloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ncccc2C(F)(F)F)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2C(F)(F)F)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-trifluoromethyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[NH:17][N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Cl[CH2:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[N:17]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (42 mg, 0.124 mmol), and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (39 mg, 0.186 mmol) in anhydrous DMF (0.5 mL) was added anhydrous potassium carbonate (34.6 mg, 0.25 mmol). The resulting suspension was stirred under argon at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting precipitate was filtered, washed with water, and dried in a vacuum oven at 60° C. for 16 h to afford 56 mg (89%) of the title compound as an off-white solid. HPLC/MS: retention time=4.15 min, [M+H]+=512.2.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[CH:35][C:34]=1[F:44]>>[F:44][C:34]1[CH:35]=[C:36]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)[CH:37]=[CH:38][C:33]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]3)=[N:14][C:13]=2[CH:30]=1
Reactant: Fc1cc(-n2cnnn2)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Yield: 4.8 %

Procedure:
Following the General Procedure-1, the titled compound (10 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4-bromo-3-fluorophenyl)-1H-tetrazole (110 mg, 0.45 mmol) as a brown solid. M.P.: 203-207° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.71-7.58 (m, 4H), 7.52 (td, 1.6, 8.4, 1H), 4.16 (d, J 10.8, 2H), 3.21-3.12 (m, 1H), 3.00 (t, J 12.2, 2H), 2.21-2.13 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[CH:34]2>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[CH:34]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 35.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (215 mg, 1.56 mmol) and 5-hydroxy-2-methylindole (162 mg, 1.10 mmol) in DMF (8.0 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with methanol (2.5 to 5%) in dichloromethane. The resulting solid was recrystallised from ethyl acetate, filtered and washed with diethyl ether to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (166 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[C:18]([O:20]C)[CH:17]=[N:16][C:15]=23)=[O:10])[CH:7]=1.C[S-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[N:16][C:15]=23)=[O:10])[CH:7]=1
Reactant: COc1cnc2c(C(=O)Nc3cc(Cl)ccc3N3CCCCC3)cnn2c1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)ccc1N1CCCCC1)c1cnn2cc(O)cnc12
Temperature: 160 °C
Yield: 26.4 %

Procedure:
A mixture of 6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5-chloro-2-piperidin-1-yl-phenyl)-amide (100 mg) and sodium methanethiolate (45 mg) in N,N-dimethylformamide (ca. 2 mL) was heated in a sealed tube at 160° C. for 48 hours. The resulting mixture was evaporated under reduced pressure and the residue was dissolved in a mixture of chloroform and methanol, absorbed onto silica gel and purified by flash chromatography (DCM/MeOH/AcOH) to give 25.4 mg (26% yield) of 6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5-chloro-2-piperidin-1-yl-phenyl)-amide as a yellow solid. MS=372 [M+H]+; MP>300° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:23]=O)=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.[NH2:26]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:23]#[N:26])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccco1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-furyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.6 g), hydroxylamine hydrochloride (383.6 mg) and sodium acetate (787.6 mg) in acetic acid (14 ml) was stirred for 30 minutes at room temperature. To the mixture, acetic anhydride (1 ml) was added and stirred for 1.5 hours at room temperature and further stirred for an hour under reflux. After removal of the acetic acid from the reaction mixture, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and water and dried, and then the solvent was distilled off under reduced pressure. The resultant brown oil (1.8 g) was purified by column chromatography on silica gel by an eluent (a mixture of 15 parts of chloroform and one part of ethyl acetate by volume). The concentrate (920 mg) of the fraction of the eluate which showed one spot on thin-layer chromatography and the concentrate of one (450 mg) which showed plural spots respectively gave crystals (totally 875 mg) and these were recrystallized from a mixture of diethyl ether and n-hexane to give pure crystals (818 mg) of diethyl 2-methyl-4-(2-furyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 139° to 141° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 73.8 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 73.8%).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:33])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:19][CH2:20][CH3:21])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:33][CH:13]([CH3:12])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH2:19][CH2:20][CH3:21])=[O:16]
Reactant: CCCC(OC(=O)CC(C)C)OC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC(OC(=O)CC(C)C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl 3-methylbutanoate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 37 (120 mg, 15% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.95 (m, 11H), 1.21-1.41 (br. m, 5H), 1.68-1.73 (m, 4H), 1.89-2.02 (m, 3H), 2.10-2.22 (m, 3H), 2.80-2.89 (m, 2H), 6.65 (t, J=5.6 Hz, 1H), 7.45 (t, J=6.0 Hz, 1H), 12.04 (s, 1H). MS (ESI) m/z 380.23 (M+Na)+; 356.18 (M−H)−.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.CO>[C:27]1([C:18]2([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:6])[CH2:20][CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Solvent: ClCCl
Solvent: CO
Product: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: -3 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 15.4 g of 3-chloroperoxybenzoic acid (at 85%) in 400 cm3 of dichloromethane is added over 40 minutes to a solution, cooled to -3° C., of 25 g of (4aRS, 7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole in 500 cm3 of dichloromethane and 100 cm3 of methanol. After stirring for one hour at -3° C., the reaction mixture is washed with 200 cm3 of a 10% aqueous solution of potassium hydrogen carbonate and again with 100 cm3 of this same solution, then dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is crystallized from 50 cm3 of ethyl acetate, the crystals are taken up in 200 cm3 of dichloromethane, the solution obtained is washed with 75 cm3 of a 1N aqueous solution of sodium hydroxide and then dried over magnesium sulphate and concentrated to dryness. The residue is crystallized from 30 cm3 of ethyl acetate, the crystals are washed with ethyl acetate, drained and dried. 13.6 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide are obtained in the form of white crystals; melting point 174° C.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1([C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2N)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.N([O-])=O.[Na+].[I-:27].[K+]>O.C(OCC)(=O)C>[I:27][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Nc1ccccc1-n1ncc2ccccc21
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1ccccc1-n1ncc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (7.67 mL, 144 mmol) was added to a solution of 2-(1H-indazol-1-yl)aniline (1.771 g, 8.46 mmol) in concentrated HCl (2.030 mL, 25.4 mmol) at 0° C. The solution was stirred and after cooling back to 0° C., sodium nitrite (0.584 g, 8.46 mmol) in water (3.5 mL) was added dropwise. The reaction was stirred 40 min at 0° C. before potassium iodide (2.81 g, 16.93 mmol) in water (3.5 mL) was added dropwise and the solution was stirred at RT. After 1 h, the reaction is poured into ice with ethyl acetate and separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with 1N HCl, water, saturated sodium bicarbonate, 1N sodium sulfite, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude material was purified by silica gel chromatography by eluting with 1:4 EtOAc in hexane, to provide 1-(2-iodophenyl)-1H-indazole.