Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(c2ccc(O)cc2)CC1

Procedure:
A mixture of 17 parts of 4-(1-piperazinyl)phenol dihydrobromide, 7 parts of ethyl carbonochloridate, 21 parts of potassium carbonate and 250 parts of 1,4-dioxane is stirred and refluxed for 48 hours. The reaction mixture is filtered, while hot and the filtrate is evaporated. The solid residue is dissolved in a diluted hydrochloric acid solution. The solution is alkalized with ammonium hydroxide. The product is filtered off and dried, yielding 3.5 parts of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate; mp. 168.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:32]4[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)cc3)o2)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)cc4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 12.4 %

Procedure:
4-{5-[(4-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (144.0 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (100.0 mg, 0.5 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (72.3 mg, 0.5 mmol) was added, followed by anhydrous K2CO3 (34.5 mg, 0.25 mmol). Then the vial was capped and microwaved at 200° C. for 15 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (24.5 mg).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[C:12]([CH3:27])[N:11]=1)([CH3:9])[CH3:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=[O:35])[CH:29]=1>C1COCC1>[CH3:9][C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]=[C:12]([CH2:27][CH:34]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[OH:35])[N:11]=1)([CH3:6])[CH3:8]
Reactant: O=Cc1cccnc1
Reactant: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(CC(O)c2cccnc2)nc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
n-Butyllithium (1.5 mL of 1.6M solution in hexane, 2.4 mmol) is added dropwise to a solution of 4,6-bis (1,1-dimethylethyl)-5-[(2-methoxyethoxy) -methoxy]-2-methylpyrimidine (750 mg, 2.4 mmol) in dry THF (12 mL) at 0° C. under an atmosphere of dry nitrogen. The reaction mixture is stirred at room temperature for 30 minutes and then cooled to -78° C. A solution of pyridine 3-carboxaldehyde (250 mg, 2.4 mmol) in dry THF (1 mL) is added dropwise. The reaction mixture is stirred at room temperature for 3 hours and then is quenched by the addition of saturated aqueous ammonium chloride. The product is extracted into ether. The organic layer is dried (MgSO4) and evaporated to give crude 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-α-(3 -pyridinyl)-2-pyrimidineethanol (500 mg, 50%) which is not further purified, but used directly in the next reaction.
Reaction SMILES: C(O)(=[O:8])CCCCCC.[OH:10][CH:11]([CH2:29][O:30][CH2:31][CH2:32][CH3:33])[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[CH2:17][S:16][CH:15]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[OH:10][CH:11]([CH2:29][O:30][CH2:31][CH2:32][CH3:33])[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[CH2:17][S:16](=[O:8])[CH:15]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCCCCCC(=O)O
Reactant: CCCOCC(O)CCN1C(=O)CSC1CCCCCCC(=O)O
Product: CCCOCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the same method as described in Example 2 except that the 7-3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]heptanoic acid is replaced by 7-[3-(3-hydroxy-4-propoxybutyl)-4-oxo-2-thiazolidinyl]heptanoic acid. This method provides the title compound as an essentially colorless, viscous oil.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: CN(C)CCN
Product: COc1ccc2c(c1)CCn1c-2cc(NCCN(C)C)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-dimethylamino-ethylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 7.81 (br, 1H), 7.78 (d, 1H), 7.01-6.95 (2H), 6.16 (s, 1H), 3.94 (t, 2H), 3.83 (s, 3H), 3.62 (br, 2H), 3.21 (br, 2H), 2.93 (t, 2H) and 2.83 (s, 6H); MS (ESI) (M+H)+ 315.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[Cl:14][C:15]1[CH:16]=[C:17](N)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:14][C:15]1[CH:16]=[C:17]([S:8]([Cl:11])(=[O:10])=[O:9])[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Product: O=S(=O)(Cl)c1ccc(C(F)(F)F)c(Cl)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 3-chloro-4-trifluoromethyl-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 10.1 %

Procedure:
In one portion, 96 g (0.75 mole) of 4-chlorophenol was added to a stirred solution of 67.5 ml (0.75 mole) of chlorosulfonylisocyanate in 400 ml of toluene. The solution was heated at 100° C. for 16 hr and the solution chilled with an ice-acetone bath and water added dropwise until evolution of gases ceased. The tan solid which precipitated from solution was collected and dried for 16 hr to yield 133.4 g. A 25 g portion was recrystallized from 100 ml of toluene to give 15.8 g of white solid, mp 103°-104° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.Cl.[CH:19]1([C:22]2[C:23]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[F:16])=[O:13])[CH2:35][CH2:36]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:20][CH2:21]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 66.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (259 mg) described in Preparation Example 23 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (280 mg) described in Preparation Example 87 and to by the reaction and treatment in the same manner as in Example 86, the title compound (323 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:10]3[C:9]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1

Procedure:
9,9-diphenylfluorene was prepared from α,α-diphenyl-2-biphenylmethanol by the following method. To a solution of the starting carbinol (0.50 g, 1.49 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (10 mL). After refluxing for 1 hour, the reaction was cautiously neutralized by the addition of aqueous NaHCO3. The mixture was then extracted with Et2O (2×100 mL) that was subsequently washed with additional H2O (100 mL) and brine, dried over MgSO4 and concentrated to white solid (0.47 g, 99% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([CH2:23][N:24]3[CH2:28][CH:27]([NH:29][C:30]([C:32]4[CH:33]=[CH:34][C:35]5[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=5[CH:42]=4)=[O:31])[CH2:26][CH:25]3[C:43](O)=[O:44])[CH2:13][C:12]2=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([CH2:23][N:24]3[CH:25]([C:43]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:44])[CH2:26][CH:27]([NH:29][C:30]([C:32]4[CH:33]=[CH:34][C:35]5[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=5[CH:42]=4)=[O:31])[CH2:28]3)[CH2:13][C:12]2=1
Reactant: C1COCCN1
Reactant: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1C(=O)O)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1C(=O)N1CCOCC1)CO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Morpholine (2 μL, 0.024 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-pyrrolidine-2-carboxylic acid (14 mg, 0.024 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by 1-hydroxybenzotriazole (4 mg, 0.027 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (5 mg, 0.028 mmol, 1.15 eq) and N,N-diisopropylethylamine (13 μL, 0.073 mmol, 3.0 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-5-(morpholine-4-carbonyl)-pyrrolidin-3-yl]-amide as a white lyophilized powder (12 mg, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[NH:1][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:13])=[O:14])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(N)c2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(NC(=O)c3ccccc3)c2c1

Procedure:
N-[5-(2-Methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]benzamide can be obtained as described in Example 28 from 0.5 g of N-(3-amino-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide, 3 ml of pyridine and 0.158 ml of benzoyl chloride. 435 mg of N-[5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl)benzamide are thus obtained in the form of a pink solid which decomposes at approximately 200° C. (analysis C21H18N4O5S2.0.22CH2Cl2 % calculated C, 53.60; H, 3.86; N, 11.91; O, 17.00; S, 13.63. % found C, 53.59; H, 3.89; N, 12.10; S, 13.53).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[CH3:36][C:37]1([CH3:65])[CH2:63][C:41]2[C:42]([C:51]3[CH:52]=[C:53]([NH:57][C:58](=[O:62])[C:59](O)=[O:60])[CH:54]=[CH:55][CH:56]=3)=[C:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[S:44][C:40]=2[C:39](=[O:64])[CH2:38]1>C(Cl)Cl>[CH3:36][C:37]1([CH3:65])[CH2:63][C:41]2[C:42]([C:51]3[CH:52]=[C:53]([NH:57][C:58](=[O:62])[C:59]([NH:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:60])[CH:54]=[CH:55][CH:56]=3)=[C:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[S:44][C:40]=2[C:39](=[O:64])[CH2:38]1
Reactant: NCCN1CCCC1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)O)c3)c2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)NCCN4CCCC4)c3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.1 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (145 mg, 0.33 mmol) and 1-(2-aminoethyl)pyrrolidine (60 μL, 0.49 mmol) were added to a solution of Example 292 (70 mg, 0.16 mmol) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 18 h. A further portion of 1-(2-aminoethyl)-pyrrolidine (60 μL, 0.49 mmol) was added and stirring was continued for 72 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (pH 2.5) to give the title compound (16 mg, 19%) as an off-white solid. δH (CDCl3) 9.26 (1H, s), 8.43 (1H, br s), 7.74-7.69 (1H, m), 7.65-7.59 (1H, m), 7.45 (1H, t, J 7.7 Hz), 7.23-7.16 (1H, m), 3.78-3.64 (6H, m), 3.11-2.92 (10H, m), 2.49 (2H, s), 2.45 (2H, s), 2.07-1.96 (4H, m), 1.05 (6H, s). LCMS (ES+) 525.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.[C:13]([OH:22])(=[O:21])[C:14]1C(=CC=[CH:19][CH:20]=1)N>>[C:8]([C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:12][CH:14]1[CH2:20][CH2:19][O:22][C:13]1=[O:21])([OH:10])=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(N)c(C(=O)O)c1
Product: COc1ccc(NC2CCOC2=O)c(C(=O)O)c1

Procedure:
In the method of the Reference Example 1, 5-methoxyanthranilic acid was reacted in the place of anthranilic acid to obtain α-[(2-carboxy-4-methoxyphenyl)-amino]-γ-butyrolactone, melting point: 206.5°-208° C.(decomp.).
Reaction SMILES: Cl[C:2]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:5]2[N:6]=[C:7]3[C:12]([C:11]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:2]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][N:5]4[N:6]=[C:7]5[C:12]([C:11]([C:13]6[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=6)=[CH:10][CH:9]=[CH:8]5)=[C:4]4[N:3]=3)=[CH:44][CH:45]=2)[CH2:37][CH2:38][CH2:39]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(Cl)nc4c23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5c(-c6ccc(C#N)cc6)cccc5nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
114 mg (0.3 mmol) 4-(2-Chloro-3-phenylpyrimido[1,2-b]indazol-10-yl)benzonitrile, 122.9 g (0.3 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester, 34.6 mg (0.03 mmol) tetrakistriphenylphosphinepalladium(0) and 95 mg (0.90 mmol) sodium carbonate in 3.2 mL dioxane and 0.45 mL water were heated in a microwave vial which had been sealed with a microwave cap over night at 105° C. (heating block). After the usual work up, the crude mixture (235 mg) was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[N:15])[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[N:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CCCC(N)C1
Reaction time: 1 h

Procedure:
(3-Cyano-cyclohexyl)-carbamic acid tert-butyl ester (0.74 g, 3.30 mmol) was dissolved in TFA/DCM and stirred for 1 hr. The solvent was evaporated to give 3-amino-cyclohexanecarbonitrile as a brown solid. The crude material was used without further purification. LCMS (Method H, ESI): RT=0.35 min, m+H=125.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH2:14])=[NH:13].O=[C:16]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][C:18](OCC)=[O:19]>CN1CCCC1=O.C(O)C>[OH:19][C:18]1[N:14]=[C:12]([NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[N:13]=[C:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CCOC(=O)CC(=O)c1cccnc1
Solvent: CCO
Solvent: CN1CCCC1=O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(O)cc(-c2cccnc2)n1
Temperature: 150 °C

Procedure:
40 g (2-methyl-5-nitrophenyl)guanidine in 160 mL N-methyl pyrrolidone is dissolved. The mixture is heated to 150° C. and ethyl β-oxo-3-pyridine propionate is added portionwise, to 50 g total in a time period of 5 hours, distillating about 15 g of by-products under a nitrogen flow. At the end of the reaction, the mixture is cooled and diluted with ethanol. The precipitate is filtrated, yielding, upon drying, 46.4 g of product with HPLC purity of 99% (A %), identified through LC-MS and 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1I.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O>[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: Brc1ccccc1I
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2Br)cc1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 1.0 g, 2.392 mmol), 1-bromo-2-iodobenzene (1.0 g, 3.588 mmol, Aldrich), Pd2(dba3)2 (138 mg, 0.239 mmol), Xantphos (437 mg, 0.478 mmol) and sodium-tert-butoxide (459 mg, 4.784 mmol) in toluene (20 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected to microwave for 1 h at 100° C. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 12% ethyl acetate in hexane) to get 4-(2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a yellow coloured solid (1.2 g, 88.2%). m/z (ESI) 571.9 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[C:7]3=[O:14].O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][CH:29]([CH3:31])[CH2:28][CH2:27][N:9]1[C:10]2[C:6](=[C:5]3[S:1][CH:2]=[N:3][C:4]3=[CH:12][CH:11]=2)[C:7](=[O:14])[C:8]1=[O:13]
Reactant: CC(C)CCBr
Reactant: O=C1Nc2ccc3ncsc3c2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)C(=O)c2c1ccc1ncsc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a stirred solution of 6H-thiazolo[5,4-e]indole-7,8-dione (2.83 g, 13.9 mmol) in a mixture of anhydrous tetrahydrofuran (120 mL) and N,N-dimethylformamide (80 mL) was added cesium carbonate (23.0 g, 70 mmol) at ambient temperature. The deep purple mixture was stirred for 0.5 h followed by the addition of 1-bromo-3-methylbutane (4.15 mL, 35.0 mmol) in one portion. The mixture was stirred at ambient temperature for 16 h and poured into 800 mL of ice-water and extracted with ethyl acetate. The orange solution was filtered through Celite, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was triturated with diethyl ether to afford 6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (2.2 g, 57%): 1H NMR (300 MHz, CDCl3) δ9.36 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 3.77-3.69 (m, 2H), 1.74-1.58 (m, 1H), 1.57-1.47 (m, 2H), 0.94 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[C:7]([Cl:19])=[N:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:10][C:11]=1Cl.[K+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([NH-:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>CS(C)=O>[CH3:35][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:11]2[C:6]([O:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[O:2][CH3:1])=[C:7]([Cl:19])[N:8]=[C:9]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:10]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: Cc1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cc1
Reaction time: 20 h
Yield: 68.5 %

Procedure:
2 g 5-(o-methoxyphenoxy)-4,6-dichloro-2-(4-pyridyl)-pyrimidine was dissolved in 30 ml dry DMSO. 2.40 g p-toluene-sulfonamide potassium salt was added and stirring continued for 20 h. The reaction mixture was poured onto 200 ml water and extracted twice with 200 ml diethylether. The combined organic layers were extracted twice with 50 ml water. The combined water layers were acidified by acetic acid to pH=4. The precipitated product was filtered off, washed with ether and dried under reduced pressure. 1.9 g p-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamide was obtained as a slightly colored solid. Rf (EA/Hex=1/1)=0.15.