Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: OB(O)c1ccccn1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccnc2)cc1
Temperature: 90 °C
Yield: 72 %

Procedure:
Scheme VI, Step A′: [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.52 mmol, prepared in example 1), pyridyl boronic acid (93 mg, 0.76 mmol), potassium carbonate (104 mg, 0.76 mmol), tetrakis(triphenyl phosphine)palladium(0) (41 mg, 0.036 mmol), and dioxane/water (20 mL, 3:1) were mixed together in a 100 mL single neck flask and stirred at 90° C. over night. In the morning, the reaction was cooled to room temperature and poured into H2O, and the desired product was extracted with ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, filtered, and concentrated under reduced pressure to yield 235 mg. of a viscous oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 1:1 to yield the title compound (126 mg, 72%) as a semi-solid. Ion spray M.S. 337.2 (M*+1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+].O>CO>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(Cl)ncc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (17.82 g, 78.2 mmol) in methanol (100 mL) stirred at 0° C. was added solid sodium methoxide (4.22 g, 78 mmol) portionwise during 5 minutes. The reaction mixture was stirred at 23° C. overnight. To the organic phase was added water (25 mL) and the methanol was removed. Then it was extracted with dichloromethane. The organic phase was dried over sodium sulphate and evaporated in vacuo to give the title compound as a white solid (17.2 g, 67.6 mmol, 86 yield). LC/MS [M+H]+=223/225.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=365.2 [M+H]+.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)=[N:3][CH:2]=1.Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28]([N:12]1[CH2:11][CH2:10][C:9]2[C:5]3[C:4]([NH:14][C:15]4[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=4)=[N:3][CH:2]=[N:1][C:6]=3[S:7][C:8]=2[CH2:13]1)=[O:29]
Reactant: Oc1cccc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cccc(O)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 3-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol from Example 16A (52 mg, 0.18 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (41 mg, 0.25 mmol) to yield 7 mg (9%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:13][NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(OCC)C>[CH3:13][N:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CNCCc1ccccn1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acryloyl chloride (4.52 g, 0.05 mole) was added dropwise to a stirring solution of triethylamine (30 ml) and 2-(β-methylaminoethyl)pyridine (6.81 g, 0.05 mole) in ethyl ether (500 ml). After stirring overnight at room temperature, the white solid was removed by filtration and washed well with ethyl ether. The organic phases were combined, dried over sodium sulfate, filtered then concentrated to dryness to give an orange oil. The structure was confirmed by NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[I:11]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: CC(=O)O
Product: N#Cc1cc(I)c(N)cc1Cl
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-2-chlorobenzonitrile (5.0 g, 33 mmol) and N-iodosuccinimide (8.4 g, 37 mmol) in Acetic Acid (35 mL) was stirred at 23° C. After 18 h, the solid was collected by filtration then purified on silica gel (0-20% EtOAc in hexanes) to afford a pale brown solid as 4-amino-2-chloro-5-iodobenzonitrile. 1H NMR (500 MHz, CDCl3) δ ppm 7.87 (1H, s), 6.77 (1H, s), 4.72 (2H, br. s.)
Reaction SMILES: ClC(=C)C#[N:4].[N:6]1([CH:14]2[CH2:21]CC[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13]CCCCCN1>C(#N)C>[C:21]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:13][N:6]=1)#[N:4]
Reactant: C=C(Cl)C#N
Reactant: C1CCCC(N2CCCCCCN2)CCC1
Solvent: CC#N
Product: Cc1ccc(C#N)nc1

Procedure:
19.6 g of 1-dimethyl-1-aza-3-methyl-1,3-butadiene, 17.5 g of 2-chloroacrylonitrile and 33.6 g of diazabicyclooctane (DABCO) are heated in 200 ml of acetonitrile for 30 hours to reflux. The reaction mixture is concentrated by evaporation and the residue is slightly acidified with 1N HCl and extracted with chloroform. The organic extract is dried and concentrated by evaporation and the residue is distilled. b.p. (6·10-3 bar) 63°-69° C. The distillate is digested with petroleum ether. The title compound is isolated in the form of crystals with a melting point of 72°-74° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)=[N:20][CH:21]=1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Reactant: Fc1ccc(Br)nc1
Product: Fc1ccc(Nc2ncc(-c3cccnc3)c3cccnc23)nc1

Procedure:
The title compound, MS: m/e=318.1 (M+H+), was prepared in accordance with the general method of example 6 step 3 from 5-pyridin-3-yl-[1,7]naphthyridin-8-ylamine and 2-bromo-5-fluoro-pyridine (Example C).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[OH-].[Na+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].Cl>O.CCOCC>[CH2:13]([O:12][C:10]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(O)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(NCC(O)CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
1-Amino-2,3-propanediol (15.2 g, 167 mmol) and NaOH (8.1 g, 204 mmol) in water (70 ml) at -10° C. was treated dropwise with benzyl chloroformate (28.5 ml, 200 mmol) in ether (30 ml) over 20 min. The reaction was stirred at 0° C. for 30 min then at room temperature for 2 h. The mixture was acidified with 2M HCl and extracted with ethyl acetate which was washed with 0.5M H3PO4 and brine, then dried over Na2SO4 and evaporated. Recrystallization of the residue from benzene afforded 16.59 g (44%) of the desired product as a white powder. NMR (300 MHz, CD3OD, ppm): 3.12 (dd, 1H), 3.28 (dd, 1H), 3.50 (m, 2H), 3.68 (m, 1H), 5.08 (s,2H), 7.35 (m, 5H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH3:35][NH2:36].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:35][NH:36][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:28])=[O:29])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCOC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.055 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.15 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (13.2 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1%/o trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (9.0 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N:24]2[CH2:25][CH2:26][N:27]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:28][CH2:29]2)[CH2:13][CH2:14]1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 103.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 6-fluoro-4-methylnicotinic acid (386 mg) and 1-(2,4-dicyclopropylphenyl)piperazine (650 mg), the title compound (980 mg) was obtained.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]([CH3:39])[S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:42][N:41]=[N:40][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([N:29]([CH3:39])[S:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=[O:2].[NH4+].[Cl-]>C(O)(=O)C.O.[Zn]>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1cccc(C(=O)O)c1
Temperature: 0 °C

Procedure:
As an alternative method of forming azo compounds, nitroso compounds are coupled to amines in glacial acetic acid by the Mills reaction. Badger, G. et al., Aust. J. Chem. 17: 1036 (1964). Nitroso compounds are made by the method of Coleman et al., Organic Synthesis Collective Vol. III: p668. For example, 3-nitrobenzoic acid (Aldrich Chem. Co., Milwaukee, Wis.) (2.44 mmoles) and a solution of 150 mg of NH4Cl in 5 ml of water are combined in a 50 ml round-bottomed flask and stirred vigorously. Zinc dust (372 mg) is added in small portions over 5 minutes. After the addition of zinc is complete the temperature begins to rise, but is kept between 50 and 55° C. by the use of an ice bath. The mixture is stirred at that temperature for 20 minutes and then the zinc residues are filtered and washed with boiling water. The combined filtrate and washings are cooled to 0° C. in a beaker by the addition of ice. To this cold mixture of the hydroxylamine, a cold solution of sulfuric acid (750 μl of concentrated acid plus enough ice to bring the temperature to −5° C.) is added with stirring. An ice-cold solution of 170 mg of sodium dichromate dihydrate in 750 μl of water is added all at once with stirring. The resulting 3-nitrosobenzoic acid thus obtained is combined with one-half of an equivalent of benzidine, 2,7-diaminofluorene or another benzidine derivative in glacial acetic acid and warmed to 70-80° C. for 7 hrs and then allowed to stand at room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate giving 4,4′-bis(3-carboxy-phenylazo)-biphenyl), 2,7-bis(3-carboxy-phenylazo)-fluorene, or the corresponding bis(3-carboxy-phenylazo) derivative of the particular benzidine derivative employed.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[C:5]([O:7]C)=O.C[O-].[Na+].Cl.[C:23]([NH2:26])(=[NH:25])[CH3:24]>CO>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][C:4]1[C:3]([OH:18])=[N:25][C:23]([CH3:24])=[N:26][C:5]=1[OH:7]
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(C)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of dimethyl-(o-methoxyphenoxy)malonate (10 g) in dry methanol (80 ml) was cooled to 0° C. Sodium methylate (6.71 g) was added portionwise. To the suspension was added of acetamidine hydrochloride (2.84 g) and the mixture was stirred overnight at r.t. The solvent was removed under reduced pressure and the residue was suspended in diethyl ether (100 ml). The solid was filtered off, washed with another portion of diethyl ether (100 ml) and dissolved in water (50 ml). The pH was adjusted to 4 by adding glacial acetic acid (25 ml). The white precipitate that formed was filtered off, washed with water and dried to yield 5-(o-methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (5.17 g) (or a tautomer) as a white powder.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([C:16]1[CH:31]=[CH:30][C:19]([O:20][CH2:21][CH:22]([OH:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[CH2:8]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:29])[CH2:23][N:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)=[CH:30][CH:31]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2cccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.24 g (12.1 mmol) acetic anhydride are mixed with 10 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.100 g (0.304 mmol) 1-(4-octylphenoxy)-3-(pyrrol-1-yl)propan-2-ol in 10 ml absolute DMSO. Having stirred for 19 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions with diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps using saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave a brownish oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 97:3) and yields the product as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]3[C:23](=[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=1[C:36]([O:38]CC)=[O:37])=[CH:11][CH:10]=[CH:9]2)(=[O:4])[CH:2]=[CH2:3].[OH-].[Na+]>O1CCCC1.CO>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]3[C:23](=[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=1[C:36]([OH:38])=[O:37])=[CH:11][CH:10]=[CH:9]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1ccc2c(OCCCc3c(C(=O)OCC)[nH]c4c(-c5ccccc5C)cccc34)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2c(OCCCc3c(C(=O)O)[nH]c4c(-c5ccccc5C)cccc34)cccc2c1

Procedure:
To a mixture of EXAMPLE 565B (62.8 mg), acrylic acid (9.91 μl) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATU, 54.9 mg) in tetrahydrofuran (3 ml) was added triethylamine (36.6 μl). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with dichloromethane, to provide ethyl 3-(3-(6-acrylamidonaphthalen-1-yloxy)propyl)-7-o-tolyl-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (500 MHz, methanol-d4) δ 8.22-8.25 (m, 2 H), 7.68 (dd, J=5.95, 3.20 Hz, 1 H), 7.59 (dd, J=9.15, 2.14 Hz, 1 H), 7.25-7.37 (m, 6 H), 7.05-7.08 (m, 2 H), 6.74 (dd, J=6.10, 2.44 Hz, 1 H), 6.46-6.55 (m, 1 H), 6.38-6.44 (m, 1 H), 5.80 (dd, J=10.07, 1.83 Hz, 1 H), 4.20 (t, J=5.95 Hz, 2 H), 3.40-3.56 (m, 2 H), 2.34 (t, J=6.71 Hz, 2 H), 2.11 (s, 3 H).
Reaction SMILES: ON=[C:3]([C:9]1[CH:13]=[N:12][S:11][N:10]=1)[C:4]([O:6]CC)=[O:5].C=[O:15].Cl>O>[S:11]1[N:12]=[CH:13][C:9]([C:3](=[O:15])[C:4]([OH:6])=[O:5])=[N:10]1
Reactant: CCOC(=O)C(=NO)c1cnsn1
Reactant: C=O
Agent: Cl
Solvent: O
Product: O=C(O)C(=O)c1cnsn1

Procedure:
A mixture of ethyl 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (a mixture of syn and anti isomers) (6.0 g.), 36% aqueous solution of formaldehyde (40 ml.), conc. hydrochloric acid (20 ml.) and water (40 ml.) was treated according to a similar manner to that of Example 6(a)(2) to give crystals of 2-(1,2,5-thiadiazol-3-yl)glyoxylic acid (1.6 g.), mp 130° to 133° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].[Cl:19][C:20]1[CH:25]=[C:24]([N+]([O-])=O)[CH:23]=[CH:22][N:21]=1>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:23]=[CH:22][N:21]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccnc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.48 gm (0.018 mol) of potassium carbonate were added in portions to a stirred solution of 2.95 gm (0.015 mol) of 2-chloro-4-trifluoromethyl-phenol and 2.2 gm (0.015 mol) of 2-chloro-4-nitro-pyridine in 10 ml of dimethylformamide, and the mixture was stirred first for 1 hour at room temperature and then for 11/2 hours at 80° C. Thereafter, the reaction mixture was poured into ice water, and the aqueous mixture was extracted with chloroform. The organic phase was separated, washed with 2N sodium hydroxide and with water, dried with sodium sulfate and evaporated, yielding the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:14]Br>C(O)C>[Br:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: Nc1ccc(Cl)nn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a 250 mL round-bottomed flask was added 6-chloropyridazin-3-amine (3.92 g, 30.3 mmol), sodium bicarbonate (5.08 g, 60.5 mmol) and ethanol (20 mL). To the resulting solution, bromine (1.559 mL, 30.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The solution was filtered and then concentrated in vacuo. The residue was dissolved in water and the product extracted with ethyl acetate (3×). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-6-chloropyridazin-3-amine (4.5 g, 21.59 mmol, 71.3% yield). LC/MS, m/z 207.88 (M+1). HPLC Rt, 1.25 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]([C:8]1[C:9]([Cl:23])=[C:10]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[S:14](=[O:20])(=[O:19])[CH2:13][CH2:12][C:11]2([CH3:22])[CH3:21])(=[O:7])C.C(OCC)(=[O:26])C>O>[Cl:23][C:9]1[C:8]([C:5]([OH:26])=[O:7])=[CH:17][C:16]([CH3:18])=[C:15]2[C:10]=1[C:11]([CH3:22])([CH3:21])[CH2:12][CH2:13][S:14]2(=[O:20])=[O:19]
Reactant: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Reactant: CCOC(C)=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)O)c(Cl)c2c1S(=O)(=O)CCC2(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
3.6 Grams (85 mmol) of sodium hydroxide was dissolved in 70 ml of water, and 1.5 ml (29 mmol) of bromine was added with cooling with ice. Further, 2.8 g (9.3 mmol) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman-1,1-dioxide was added, and the mixture was stirred for 3 hours and then heated at 100° C. for 5 hours. After the completion of the reaction, ethyl acetate was added, and the mixture was liquid-separated. An aqueous layer was adjusted to a pH of 1 by adding hydrochloric acid. The extraction of the aqueous layer was carried out by adding ethyl acetate, and an organic layer was dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to give 2.1 g (yield 75%) of 5-chloro-4,4,8-trimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[OH:22].[CH:23](N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[Br:1][C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[O:22][CH3:23]
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1O
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
(7-Bromo-3-chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (7.0 g) was dissolved in 1-methyl-2-pyrrolidinone (35 ml) and di-isopropylethylamine was gradually added. The reaction solution was warmed at 80° C. for 3 hours. Then water (350 ml) was added. The reaction solution was stirred at room temperature for 30 minutes. The product was extracted into ethyl acetate. The organic phase was washed with 1M hydrochloric acid and a solution of sodium sulphate, evaporated and dried in vacuum. The product was purified by flash chromatography using heptane-ethyl acetate as an eluent.