Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl.CN(C1C=CC=CN=1)C>[CH2:24]([O:23][C:21]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 6-nitroindoline (10.0 g, 0.061 mol), triethylamine (22.7 mL, 0.16 mol) and dimethylaminopyridine (50 mg, cat.) in dichloromethane (130 mL) was stirred at 0° C. and benzyl chloroformate (18 mL, 0.12 mol) was added slowly. The mixture was allowed to warm to room temperature overnight. The mixture was washed with water (50 mL), 5% aqueous HCl (100 mL), saturated aqueous NaHCO3 (50 mL) and water (50 mL). The dichloromethane was dried (MgSO4) and evaporated under reduced pressure to give an orange solid. This was triturated in diethyl ether (150 ml) to give a yellow solid (12.34 g, 68%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>C(O)(=O)C.O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:14])=[C:13]([I:15])[C:8]=3[N:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc2c(c1)nnn2CC1CC1
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(nnn2CC2CC2)c1I
Reaction time: 0.25 h

Procedure:
1-(Cyclopropylmethyl)-1H-benzotriazol-5-ol (5.41 g, 28.6 mmol) was dissolved in acetic acid (75 mL) and treated with N-iodosuccinimide (4.79 g, 21.3 mmol, 0.74 equiv) portionwise. After 15 minutes, the mixture was diluted with water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2>>[N:21]12[CH2:22][CH2:23][CH2:24][C:17]1([CH2:16][NH:1][C:2]1[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20]2
Reactant: ClCC12CCCN1CCC2
Reactant: Nc1cccc2c([N+](=O)[O-])cccc12
Product: O=[N+]([O-])c1cccc2c(NCC34CCCN3CCC4)cccc12
Yield: 45.3 %

Procedure:
1-Amino-5-nitronaphthalene and 5-chloromethyl-1-azabicyclo[3.3.0]octane were reacted in the same manner as in Example 3 to obtain the titled compound in a yield of 45.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][O:58][CH:59]1[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH2:72][NH:73][CH3:74])=[CH:68][CH:67]=2)[CH2:60]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:73]([CH2:72][C:69]3[CH:68]=[CH:67][C:66]([CH2:65][N:61]4[CH2:62][CH2:63][CH2:64][CH:59]([O:58][CH3:57])[CH2:60]4)=[CH:71][CH:70]=3)[CH3:74])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (30 mg, 0.16 mmol), HOBt (23 mg, 0.17 mmol), DIPEA (0.04 mL, 0.22 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (39 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][N:2]([CH:14]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[C:18]1=[O:31])[CH2:15][CH3:16])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[ClH:32].O1CCC[CH2:34]1>>[ClH:32].[CH3:1][N:2]([CH:14]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[C:18]1=[O:31])[CH2:15][CH3:16])[CH2:3][C:12]1[C:7]2[C:8](=[CH:13][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][C:11]=1[CH3:34]
Reactant: C1CCOC1
Reactant: CCC(N1CCc2cc(OC)c(OC)cc2C1=O)N(C)c1c(C)ccc2ccccc12
Agent: Cl
Product: CCC(N(C)Cc1c(C)ccc2ccccc12)N1CCc2cc(OC)c(OC)cc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 1.3 g (3 mmol) of 2-[N-methyl-N-(2-methyl-naphth-1-yl)-amino-prop-3-yl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-one in 50 ml of tetrahydrofuran, 4.5 ml of a 1 molar borane-tetrahydrofuran complex in tetrahydrofuran are added and 0.55 ml (4.5 mmol) of boron trifluoride-diethyl etherate complex are added dropwise with stirring at ambient temperature. After 3 hours' reaction time, 5 ml of 6 molar hydrochloric acid are added dropwise, the mixture is refluxed for 0.5 hours and then the solvent is evaporated off in vacuo. The aqueous portion remaining is made alkaline with 2 molar sodium hydroxide solution and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, evaporated down in vacuo and purified over a silica gel column (0.063-0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%). The hydrochloride is precipitated from a solution in acetone with ethereal hydrochloric acid and is then recrystallised from acetone.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])[C:27]([Cl:44])=[CH:26][N:25]=1>>[Cl:44][C:27]1[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])=[N:29][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[C:6]([CH3:19])([CH3:20])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:25][CH:26]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CC(NC(=O)C(F)(F)F)C(=O)Nc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)C(F)(F)F)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2,2,2-trifluoro-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (67 mg, 24%) LCMS 564.12 (M-C3NH4), 1H-NMR (CDCl3, 400 MHz) δ 9.71 (bs, 1H), 9.60 (d, J=7.9 Hz, 1H), 9.43 (bs, 1H), 9.20 (s, 1H), 8.93 (bt, 1H), 7.50-7.47 (m, 2H), 7.37-7.34 (m, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.17 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 4.26-4.22 (m, 4H), 4.03-3.99 (m, 2H), 2.18-2.13 (m, 2H), 1.35 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [C:1]([C:5](=[CH:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:6]([O:8]C)=O)(=[O:4])[CH2:2][CH3:3]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:5]1[C:6](=[O:8])[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C(=CNc1ccccc1OC)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Yield: 53.1 %

Procedure:
Methyl 2-propanoyl-3-(2-methoxyphenylamino)acrylate (77.7 g, 0.29 mol) was added to boiling diphenyl ether (500 ml) then heated at reflux for 1 hour. The solution was partially cooled and poured into high-boiling petroleum ether, then the solid filtered off and washed with 40-60 petroleum ether to give 3-propanoyl-8-methoxy-4(1H)-quinolone (35.6 g, 52%), m.p. 260°-263°.
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[S:6][C:5]1=[O:14])(=O)C>ClCCCl>[Cl:13][C:12]1[C:7]2[S:6][C:5](=[O:14])[NH:4][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)n1c(=O)sc2c(Cl)cccc21
Solvent: ClCCCl
Product: O=c1[nH]c2cccc(Cl)c2s1
Yield: 90 %

Procedure:
Prepared analogous to Example 2(b) from 3-acetyl-7-chloro-2(3H)-benzothiazolone with a yield of 90% of theory. M.p. 202°-203° C. (1,2-dichloro-ethane).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]([NH2:29])([CH3:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]([CH3:28])([NH:29][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncnc2sc3c(c12)CCCC3
Product: CC1(Nc2ncnc3sc4c(c23)CCCC4)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared (373.9 mg, 93%) from 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (224 mg, 1 mmol) and 4-amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (235.4 mg, 1.1 mmol) by following the procedure described for preparation 9. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.39 (s, 1H), 3.33 (m, 4H), 3.10 (m, 2H), 2.87 9M, 2H), 1.93 (m, 4H), 1.66 (m, 4H), 1.40 (s, 9H), 1.22 (s, 3H); MS (SEI): m/z: Calculated: 402.6; Observed: 403.2 (M++1).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]([CH3:12])=O>>[CH3:9][C:10]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: CC(C)=O
Reactant: Oc1ccccc1O
Product: CC1(C)Oc2ccccc2O1

Procedure:
As depicted in Scheme 3, catechol was cyclized with acetone under catalytic conditions, affording the corresponding 2,2-dimethylbenzo[d]1,3-dioxolane (C1). Intermediate (C1) was then treated with for example lead tetraacetate ubder acidic conditions, yielding the corresponding 2,2-dimethylbenzo[3,4-d]1,3-dioxolan-5-yl acetate (C2). Intermediate (C2) was then deprotected with strong base, providing a phenolic intermediate (C3), which was in turn reacted with intermediate (B5), as taught in scheme 2, affording a compound of formula I. Example 3 set forth below describes in detail the method by which compounds of formula I were prepared as shown in scheme 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([CH2:19][C:10]2[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:25])[CH:4]=3)[CH:9]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)ccc1F

Procedure:
Following the procedure of Example 1(10), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a slightly yellow oil (yield: 97.5%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]([C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1CO)[CH3:26]>C1COCC1>[CH3:26][O:25][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH2:1][Br:5]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(OC)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CBr)c1
Reaction time: 2 h

Procedure:
Carbon tetrabromide (0.47 g, 1.25 mmol) and triphenylphosphine (0.47 g, 1.25 mmol) were added to a solution of 2,5-dimethoxylbenzylalcohol (0.2 g, 1.19 mmol) in THF (10 ml) at room temperature. The mixture was stirred for two hours to form a precipitate which the preciptate was filtered off. The filtrate was evaporated and the crude product was chromatographed (ethyl acetate and hexane 7:3). The desired compound was isolated as a white solid (0.25 g, 93%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:37]2[CH2:42][C@H:41]([CH3:43])[O:40][C@H:39]([CH3:44])[CH2:38]2)=[C:22]([F:36])[C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[N:32][CH:31]=[C:30]([Cl:34])[N:29]=3)[C:24]=2[CH:35]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)C.CCOC(C)=O>[Cl:34][C:30]1[N:29]=[C:28]([C:25]2[C:24]3[CH:35]=[C:20]([CH2:19][OH:18])[C:21]([N:37]4[CH2:42][C@H:41]([CH3:43])[O:40][C@H:39]([CH3:44])[CH2:38]4)=[C:22]([F:36])[C:23]=3[O:27][N:26]=2)[CH:33]=[N:32][CH:31]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(-c4cncc(Cl)n4)noc3c2F)C[C@H](C)O1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2c(CO)cc3c(-c4cncc(Cl)n4)noc3c2F)C[C@H](C)O1
Temperature: 70 °C

Procedure:
5-((tert-Butyldiphenylsilyloxy)methyl)-3-(6-chloropyrazin-2-yl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole (Intermediate 329, 320 mg, 0.51 mmol) was dissolved in ethanol (10 ml) and was treated with 15 ml of 10% aq HCl, the mixture was heated at 70° C. for 1 hour. The reaction was cooled and diluted with EtOAc before being quenched with aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc, which was washed with brine, dried (MgSO4) and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[C:12](=[C:14]([C:18]#[N:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[C:12](=[C:14]([C:18]([NH2:19])=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: O
Reactant: COc1ccc(-c2nc3c(C#N)cccc3s2)cc1
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3s2)cc1

Procedure:
A mixture of EXAMPLE 1D (0.8 g) in polyphosphoric acid (8 mL) was stirred at 100° C. for 3 hours. The mixture was cooled, treated with water and extracted with dichloromethane. The solid that precipitated out of the organic layer was filtered, washed with water and dried to afford the title compound. 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.18-8.21 (m, 1H), 8.11-8.14 (m, 2H), 7.94 (s, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.15-7.19 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([SH:15])[N:9]=[C:8]([CH3:16])[C:7]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3][CH3:4]>[Zn].C(O)(=O)C>[NH2:12][C:11]1[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]([CH3:16])=[N:9][C:10]=1[SH:15]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(S)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCNc1c(N)c(S)nc(C)c1C(=O)OCC

Procedure:
6.2 g. of 4-butylamino-6-mercapto-2-methyl-5 -nitropyridine- 3-carboxylic acid, ethyl ester (0.02 mol.) are dissolved in 25 ml. of acetic acid at reflux temperature with stirring. Zinc dust is added cautiously in small portions until the solvent is colorless. The inorganic preceipitate is then filtered off, the solvent removed and the residue dissolved in 10 ml. of methanol. The product, 5-amino-4-butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester, precipitates after the addition of aqueous ammonia, yield 3.6 g. (64%); m.p. 103°-105° (ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:14][CH:11]2[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)cc1)NC1CC1
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, tetrahydrofuran (80 ml) was added to 4-bromophenyl isocyanate 30 (10.0 g), and a solution of cyclopropylamine 1 (3.17 g) in tetrahydrofuran (20 ml) was added dropwise with stirring under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 3 hrs, and the reaction mixture was concentrated under reduced pressure. Diethyl ether-hexane [1:1 (volume ratio), 100 ml] was added to the residue and, after stirring, the crystals were collected by filtration and dried to give 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g, over weight) as colorless crystals, which were used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:16][CH3:17].CC(OC([NH:25][C@H:26]([CH2:30][CH3:31])[C:27](O)=[O:28])=O)(C)C.CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[NH2:25][C@H:26]([CH2:30][CH3:31])[C:27]([NH:15][C:12]1[CH:13]=[N:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:16][CH3:17])[CH:4]=2)=[CH:10][CH:11]=1)=[O:28]
Reactant: COc1cc(Oc2ccc(N)cn2)ccc1C
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 0 °C
Yield: 119.3 %

Procedure:
6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinamine (Intermediate 50, 500 g), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (530 g) and Et3N (905 mL) are mixed together in ethyl acetate (2 L) and stirred at 0° C. until complete dissolution. ®T3P (2.15 L) was added dropwise in 30 minutes maintaining the temperature at ˜0° C. Ethyl acetate (500 mL) was added for washing the line. Work-up: 10% w/w sodium carbonate aqueous solution (2.5 L) was added and the mixture was stirred for 20 minutes. Then water (1.5 L) and ethyl acetate (1 L) were added and the two phases separated. The organic layer was washed with 10% w/w sodium carbonate aqueous solution (2.5 L), stirring the mixture for 10 minutes before separation of phases, then with 28% malic acid aqueous solution (2.5 L) and finally with 20% NaCl aqueous solution (2.5 L). The organic solution was concentrated to the lowest volume (<2 L), acetonitrile (5 L) was added, the solution was concentrated to the lowest volume (<2 L) and acetonitrile was added up to 12.5 L (it is a solution of Intermediate 64 in acetonitrile). To this solution, 5-6N HCl solution in Isopropanol (2.5 L) was added at 20° C. and the resulting reaction mixture was stirred at 45° C. for 1.5 hours. The obtained suspension was cooled to 20° C., stirred for 1 hour and then filtered. The collected solid was washed with 5/1 acetonitrile/Isopropanol (3×1.5 L), then dried under vacuum at 40° C., until constant weight, obtaining the title compound (817 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:16]1[C:25]2[C:24]3[CH:26]=[CH:27][O:28][C:23]=3[CH2:22][CH2:21][C:20]=2[N:19]=[C:18]([NH2:29])[N:17]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:29][C:18]4[N:17]=[CH:16][C:25]5[CH2:24][CH2:26][C:27]6[O:28][CH:23]=[CH:22][C:21]=6[C:20]=5[N:19]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1ncc2c(n1)CCc1occc1-2
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: O=C(Nc1ncc2c(n1)-c1ccoc1CC2)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 5,6-dihydrofuro[3,2-f]quinazolin-3-amine (37 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 375.4, found 375.1 (M+1)+. Retention time 2.61 minutes.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:29])([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:30]([O-])=O)C1C=CC=CC=1>[H][H].[Pd]>[CH3:1][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:29])([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[NH2:30]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(Cc2nnn[nH]2)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1ccc(C(C)(Cc2nnn[nH]2)C(=O)N2CCCC2)cc1N

Procedure:
Prepared analogously to Example 1f from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one and hydrogen/palladium on activated charcoal.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: CCCNCCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(CCC)CC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), N-propylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 325 (M+, 1), 296 (7), 131 (4), 115 (10), 114 (bp), 86 (6).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH:22]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:27]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:29])=[O:28])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Reactant: O=S(=O)(Cl)C1CCCC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CCCC2)c2n(c1=O)CCS2
Yield: 113.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.2 g, 0.048 mmol) in pyridine (2 mL) was reacted with cyclopentanesulfonyl chloride (106 mg, 0.528 mmol) to afford the crude product. Purification by preparative HPLC afforded 0.03 g of the product (11% yield).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)C.O[Li].O>C1COCC1.O>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:24])=[O:3])[C:11]=3[CH:12]=2)[S:21]1
Reactant: CCOC(=O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Reaction time: 15 h
Yield: 89.9 %

Procedure:
3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic acid ethyl ester (205 mg, 0.6 mmol) (example 71) were dissolved in THF/water 4:2. To this solution was added under stirring 81 mg (4 eq.) of LiOH.H2O. The reaction was stirred for 15 h. The solvents were evaporated, and the residue was precipitated with ether. The solid was washed with 1NHCl and dried to afford 170 mg (90%) of pure 3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic acid.