Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([B:22]([OH:25])[OH:23])[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Fc1ccc(Oc2cc(F)cc(Br)c2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(Oc2ccc(F)cc2)c1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 6, using 9.1 grams (0.032 mole) of 3-fluoro-5-(4-fluorophenoxy)phenyl bromide, 14 mL (0.035 mole) of n-butyllithium (2.5M in hexanes), and 10.4 mL (0.095 mole) of trimethyl borate in 100 mL of tetrahydrofuran, yielding 3-fluoro-5-(4-fluorophenoxy)phenylboronic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].[K+].[Br-]>ClCCl>[C:11]([C:2]([C:11](=[O:14])[CH:12]=[CH2:13])([CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10])[N:1]([C:11](=[O:14])[CH:12]=[CH2:13])[C:11](=[O:14])[CH:12]=[CH2:13])(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: NCCNCCNCCN
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: C=CC(=O)N(C(=O)C=C)C(CNCCNCCN)(C(=O)C=C)C(=O)C=C
Temperature: 25 °C

Procedure:
Triethylene tetramine (2.93 g, 0.02 moles) in dichloromethane (100 ml) was added drop wise over 6 hrs to a solution of acryloyl chloride (7.24 g, 0.08 moles) in dichloromethane (40 ml), stirring vigorously at room temperature. The reaction was stirred at room temperature overnight and the suspension was filtered. The filtrate was extracted with NaOH(aq). The water was rotary evaporated and the residue was washed with acetone and filtered. The acetone washings were concentrated down and the yellow oil remaining was put through a silica gravity chromatography column with acetone as the elutant. A yellow solid was obtained and recrystallized with cold diethyl ether to give white crystals, m.p. 107-109.5° C. 1H n.m.r (D2)) δ6.60(4 H, m) CH═CH2;6.16 (6 H, m), CH═CH2; 5.79(2 H, m), CH═CH2;3.61 (6 H, m) N—CH2—CH2,3.52(6 H, m) N—CH2—CH2. 13C n.m.r (D2)) δ172.52, 172.39, 171.78, 171.70 (C═O); 132.70, 132.55, 132.14, 131.74 (CH═CH2), 130.52, 130.32, 129.93, 129.64 (CH═CH2), 50.35, 49.82, 49.35, 48.31, 47.33, 46.05 (NH—CH2—CH2). MS: mz: 363.2 (MH+, 100%), 291.2 (16), 238.1(6), 195.1(74); HRMS: found:363.20204; C18H26N4O4 requires: 362,4236Elemental analysis: found: C, 59.71; H, 7.22; N, 15.37; C18H26N4O4 requires C, 59.65; H, 7.23; N, 15.46. L.R. (KBr) (cm−1): 3283, 3423, 1672, 1642, 1552, 1278.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C(N)C.[Cl:24]CCCl>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][N:10]=1)[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Reactant: ClCCCl
Agent: CCN
Agent: CN
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(tert-Butoxycarbonyl-methyl-amino)-nicotinic acid (12.5 g, 47.0 mmol) [prepared analogously to A-05 using methylamine in stead of ethylamine] is taken up in 300 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (10.0 mL, 74.8 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:3][CH2:2]1.[H][H]>[Pt]=O.C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:3][CH2:2]1
Reactant: C1=C(c2ccc3[nH]ccc3c2)CCNC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: c1cc2cc(C3CCNCC3)ccc2[nH]1
Yield: 37.9 %

Procedure:
A mixture of 5-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole (3.4 g), platinum oxide (0.2 g) and acetic acid (50 mL) was shaken at room temperature for 24 h and under 3 atmospheres of hydrogen. The mixture was filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography on silicagel (eluent: 4 M ammonia in methanol) to give the title compound (1.3 g).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>O1CCOCC1.O>[C:7]1([CH:2]([NH:1][S:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])(=[O:26])=[O:25])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1.15 g of 3-amino-3-phenylpropionic acid are dissolved in 25 ml of dioxane and 7 ml of 1N sodium hydroxide and 1.95 g of 2,4,6-trichlorobenzenesulphonyl chloride in 5 ml of dioxane are gradually added, while. maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 100 ml of water, extracted twice with EtOAc and acidified to pH=2 by addition of 6N HCl. The solid formed is drained, washed with water and dried at 40° C. 2.09 g of the expected product are obtained, m.p.=218-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)nc1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=308.2 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-5-methylpyridine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[CH2:16]([N:23]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27](Br)[CH:28]=[CH:29][CH:30]=2)[CH2:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:35]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:28]=[CH:29][CH:30]=2)[CH2:25]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 96 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 96% yield, starting from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole and (2R)-N,N-dibenzyl-8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine: MS (ESI) m/z 408[M+H+].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)cc(-c2ccccc2)c1

Procedure:
To a solution of methyl 3-benzyloxy-5-phenylbenzoate (10 g) in acetic acid (300 ml) was added 10% palladium on carbon (1 g), and the mixture was subjected to catalytic hydrogenation at 80° C. under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. To the residue were added ethyl acetate and water, and adjusted to pH 5 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 3-hydroxy-5-phenylbenzoate.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[C:12]([CH:14]=[C:15]3[CH2:20][C@@H:19]([OH:21])[CH2:18][CH2:17][C@:16]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2)=[O:13].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:40]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41]1>>[O:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1[O:21][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C:15](=[CH:14][C:12](=[O:13])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:20]1
Reactant: C1=COCCC1
Reactant: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C[C@]12CC[C@H](OC3CCCCO3)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3β-hydroxyandrost-5-ene-7,17-dione (2) (0.5 g, 1.65 mmol) was placed in a dried, argon-flushed flask where it was dissolved in dry dichloromethane (20.0 mL). Pyridinium toluene-p-sulfonate (0.043 g. 0.17 mmol) was added followed by 3,4-dihydro-2H-pyran (0.23 mL, 2.5 mmol) and the solution was stirred at room temperature, under an atmosphere of argon, for 2-3 h. The reaction was quenched by adding water and the product was extracted thrice with ether (3×20 mL). The combined ether extracts were washed with dilute acetic acid, water and bicarbonate solution and dried (MgSO4). Solvent was removed and the crude product was purified using chromatography on silica gel (ethyl acetate-hexane, 15:85, v/v). The compound first eluted was identified as androsta-3,5-diene-7,17-dione (0.150 g), m.p. 167-8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:20])[CH:10]=[C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])(=[O:24])=[O:23]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:20])[C:10](=[C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH:15]2)[C:28]([C:27]2[CH:26]=[C:25]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:33]=[CH:32][CH:31]=2)=[O:29])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(C=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Product: O=C(C(C(=O)c1cccc(S(=O)(=O)Cl)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1

Procedure:
1-(3,5-Difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone and 3-(chlorosulfonyl)benzoyl chloride were heated under reflux in dioxane for 1 hour, followed by cooling. After dilution with ethyl acetate, the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. This was further diluted with ethyl acetate, washed with an aqueous saturated sodium hydrogencarbonate solution and water successively, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonyl chloride.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51](O)=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:27]=[C:28]([F:30])[CH:29]=1.C(N(C(C)C)C(C)C)C.[CH3:64][NH:65][CH2:66][CH2:67][OH:68]>CN(C=O)C>[F:30][C:28]1[CH:27]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51]([N:65]([CH2:66][CH2:67][OH:68])[CH3:64])=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Reactant: CNCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
TBTU (108 mg, 0.34 mmol) was added in one portion to a stirred solution of 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (0.103 mL, 0.59 mmol) and 2-(methylamino)ethanol (0.027 mL, 0.34 mmol) in DMF (1 mL). The resulting solution was stirred at RT for 2 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (90 mg, 64%) as a off-white solid. Mass Spectrum: M+H+ 502. NMR Spectrum (DMSOd6 at 323° K): 1.58 (d, 3H), 2.65 (s, 3H), 3.01 (s, 3H), 3.23-3.40 (m, 5H), 3.4-3.71 (m, 7H), 4.74 (bs, 1H), 5.52 (s, 1H), 5.57 (q, 1H), 6.38 (t, 1H), 6.53 (d, 2H), 7.74 (bs, 1H), 7.93 (s, 1H).
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]\[C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[S:16][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH2:11][CH2:12][C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[S:16][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(/C=C\c3cccc4ccccc34)cs2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCc3cccc4ccccc34)cs2)CC1
Yield: 98.2 %

Procedure:
tert-Butyl 4-{4-[(Z)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-3, 1.5 g) is dissolved in 90 ml of methanol and, at 30° C., hydrogenated under a hydrogen pressure of 10 bar using 10% Pd/C as catalyst. Removal of the catalyst by filtration and removal of the solvent under reduced pressure gives tert-butyl 4-{4-[2-(naphthalen-1-yl)ethyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.48 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:47])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[O:43][CH:44]=[CH:45][N:46]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:47])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[O:43][CH:44]=[CH:45][N:46]=3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccccc1-c1ncco1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1-c1ncco1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.5 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (125 mg, 0.25 mmol) in 2.0 mL of THF under nitrogen atmosphere at 0° C. was added drop-wise 0.3 ml (0.6 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 20 min at 0° C. followed by addition of N-Methoxy-N-methyl-2-oxazol-2-yl-benzamide (100 mg, 0.43 mmol). The mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride and extracted with ethyl acetate. After concentration the residue was purified by flash chromatograph (30% ethyl acetate in hexane) to afford 30 mg of title compound as an off white solid. MS: (M+H)/z=586.1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[OH-].[Na+].[CH3:17][N:18]=[C:19](SC)[S:20][CH3:21]>C(O)C>[CH3:17][NH:18][C:19](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:20][CH3:21]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CN=C(SC)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC

Procedure:
One g. of the oxalate salt of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole was dissolved in 10 ml. of denatured ethanol and 4.8 ml. of 1N sodium hydroxide solution. To the mixture was added 0.36 g. of methylcarbonimidodithioic acid, dimethyl ester, and the reaction mixture was stirred under reflux for 16 hours. The mixture was then evaporated under vacuum, and the residue was taken up in 12 ml. of water and 1.5 ml. of 50% aqueous sodium hydroxide. The solution was extracted twice with 25 ml. portions of diethyl ether, and the organic layers were combined, dried over potassium carbonate and evaporated under vacuum to obtain 0.65 g. of the desired product in crude form. It was identified by nuclear magnetic resonance analysis as being identical to the product of Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]2[CH:10]=[CH:9][NH:8][CH:4]2[N:5]=[CH:6][N:7]=1.[N+:11]([C:14]1[CH:15]=[C:16]([OH:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[O:23][C:2]1[CH:3]2[CH:10]=[CH:9][NH:8][CH:4]2[N:5]=[CH:6][N:7]=1)([O-:13])=[O:12]
Reactant: ClC1=NC=NC2NC=CC12
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccc(OC2=NC=NC3NC=CC23)cc1[N+](=O)[O-]

Procedure:
4-Chloro-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine (1.66 g, 10.8 mmol), 3,4-dinitrophenol (2.4 g, 13 mmol) and TFA/TEA were heated at 150° C. for 2 h. The resulting green solid was purified on silica gel using a Hexane/EtOAc gradient (100/0 to 50/50) to give 4-(3,4-dinitro-phenoxy)-7,7a-dihydro-4aH-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1.[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:12]([NH:20][C:21]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCC(=O)c2sccc21
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)NC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
A solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine (8.02 g) in methylene chloride (75 ml) is added to a stirred solution of benzoyl isocyanate (7.0 g) in methylene chloride (75 ml) under a nitrogen atmosphere. The mixture is stirred for an overnight period at room temperature and the title compound is collected by filtration. Recrystallization of the crude product from acetone/hexane affords 5.7 g of the title compound, m.p. 204° to 207° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH:13](=[N:5][CH2:4][CH2:3][CH2:2][Br:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCBr
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: BrCCCN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
The hydrobromide salt of 3-bromopropylamine (5.364 g, 24.50 mmol) was treated with triethylamine (4 mL) in CHCl3 (100 mL) and allowed to stir at room temperature for 5 min. Benzaldehyde (2.000 g, 18.85 mmol) and magnesium sulfate (6.000 g) were added and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was filtered and the filter pad was washed with CHCl3 (50 mL). The filtrate was washed with water (3×50 mL), sat NaCl (50 mL), dried over sodium sulfate, and concentrated to provide a yellow oil (4.262 g, 100%). IR (film) 1645, 754, and 693 cm−1; 1H NMR (CDCl3) δ 8.34 (s, 1H), 7.76 (m, 2H), 7.44 (m, 3H), 3.78 (dt, J=6.3 Hz and 1.3 Hz, 2H), 3.52 (t, J=6.5 Hz, 2H), 2.31 (pent, J=6.4 Hz, 2H); ESIMS m/z (rel intensity) 226/228 (MH+, 100/91). Anal. (C10H12BrN) C, H, N.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=1)(=[O:17])=[O:16])C)C1C=CC=CC=1.N>[Pd].C(O)C>[ClH:1].[CH3:2][NH:9][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=1)(=[O:17])=[O:16]
Reactant: CN(CCCNS(=O)(=O)c1cn(C)cn1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N
Solvent: CCO
Product: CNCCCNS(=O)(=O)c1cn(C)cn1

Procedure:
15 g (41.7 mmol) of N-[3-(N-benzyl-N-methylamino)-1-propyl]-1-methyl-4-imidazolesulfonamide hydrochloride from Example 28 are hydrogenated in a solution of 100 ml of 25% strength ammonia solution and 100 ml of ethanol in the presence of 2 g of 10% strength Pd/C catalyst. After completion of the absorption of hydrogen and filtering off the catalyst, the filtrate is evaporated in vacuo. The residue is recrystallized from ethanol in order to give the title compound of melting point 169°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7]C(=O)[C:5]2=[O:13].[OH:14]O>>[NH2:7][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:13])=[O:14]
Reactant: OO
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Product: Nc1cc(F)c(F)cc1C(=O)O

Procedure:
In accordance with the above reaction scheme, an aqueous solution of 3,4-difluoroaniline (I) and hydroxylamine hydrochloride containing hydrochloric acid is reacted with an aqueous solution of chloral hydrate and sodium sulfate at the reflux, then filtered while hot, giving N-(3,4-difluorophenyl)-2-(hydroxyimino)-acetamide (II). The compound (II) is reacted with concentrated sulfuric acid with heat, then added to cracked ice, giving 5,6-difluoro-1H-indole-2,3-dione (III). A basic aqueous solution of compound (III) is treated with hydrogen peroxide and heat, then cooled and acidified, giving 2-amino-4,5-difluorobenzoic acid (IV). The compound (IV) is added to a mixture of anhydrous copper(II) chloride, t-butyl nitrite and anhydrous acetonitrile at 0°-5° C., then added to a dilute mineral acid, giving 2-chloro-4,5-difluorobenzoic acid (V).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[C:11](OC)(=[O:14])[C:12]#[CH:13]>CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]2[C:3]=1[N:10]=[CH:13][CH:12]=[C:11]2[OH:14]
Reactant: COc1ccc(N)c(F)c1
Reactant: C#CC(=O)OC
Solvent: CO
Product: COc1cc(F)c2nccc(O)c2c1
Temperature: 50 °C
Yield: 32.2 %

Procedure:
2-Fluoro-4-methoxyphenylamine (3.80 g, 26.7 mmole) and methyl propiolate (2.37 ml, 0.267 mole) in methanol (100 ml) was stirred for 72 hours at room temperature, then heated at 50° C. for 24 hours. It was evaporated and the product purified by chromatography on silica gel (dichloromethane) to give a solid (1.66 g), a portion of which was recrystallised from dichloromethane-hexane. The unsaturated ester (0.96 g) in warm Dowtherm A (5 ml) was added over 3 minutes to refluxing Dowtherm A (15 ml), and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipitate was filtered to give the title compound (0.50 g, 61%). MS (ES) m/e 196 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]O)[N:6]=1.BrC1C=C(F)C(C[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=C(F)C=1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:6]=1
Reactant: OCc1csc(Br)n1
Reactant: Fc1cc(Br)cc(F)c1CN1CCCCC1
Product: Brc1nc(CN2CCCCC2)cs1

Procedure:
The title compound was prepared from (2-bromothiazol-4-yl)-methanol, following the procedure outlined above for 1-(4-bromo-2,6-difluoro-benzyl)-piperidine, to afford the title compound as a yellow oil. 1H NMR (CDCl3, 300 MHz): 7.09 (s, 1H), 3.61 (d, J=0.9 Hz, 2H), 3.19 (t, J=5.4 Hz, 1H), 2.45 (t, J=5.1 Hz, 4H), 1.69-1.62 (m, 4H), 1.48-1.41 (m, 2H). LCMS (Method B): RT=0.8 min, M+H+=261/263.