Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:21][CH2:20][CH2:19][O:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26]([N:29]2[CH2:44][CH2:43][C:31]3([N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][CH2:32]3)[C:30]2=[O:45])=[CH:25][CH:24]=1>>[CH3:14][N:13]([CH3:15])[C:11]([C:9]1[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)[C:6]2[N:7]=[C:2]([NH:22][C:23]3[N:28]=[CH:27][C:26]([N:29]4[CH2:44][CH2:43][C:31]5([N:35]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:34][CH2:33][CH2:32]5)[C:30]4=[O:45])=[CH:25][CH:24]=3)[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCN(c1ccc(N)nc1)C2=O
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCC5(CCCN5C(=O)OC(C)(C)C)C4=O)cn3)nc2n1C1CCCOC1
Yield: 71.9 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (76 mg, 0.246 mmole) was combined with tert-butyl 7-(6-aminopyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (82 mg, 0.246 mmole) which gave tert-butyl 7-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (107 mg) in 72% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.80 (s, 1H), 8.69-8.57 (m, 2H), 8.35-8.25 (m, 1H), 6.54 (s, 1H), 4.63-4.52 (m, 1H), 4.06-3.88 (m, 2H), 3.86-3.70 (m, 2H), 3.64-3.46 (m, 2H), 3.18 (S, 6H), 3.02-2.84 (m, 1H), 2.84-2.59 (m, 1H), 2.24-1.99 (m, 6H), 1.96-1.79 (m, 3H), 1.77-1.52 (m, 1H), 1.48 (s, 4H), 1.39 (s, 5H). HR-MS m/z 605.3210 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:44])=[C:4]([S:9]([N:12]([CH2:28][C:29]2[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=2)[CH2:32][NH:33]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][C:31]1[CH:30]=[C:29]([CH:43]=[CH:42][CH:41]=1)[CH2:28][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:44])(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichloro-N-(4-(4-fluorophenoxy)benzyl)-2-hydroxyphenylsulfonamido)methyl)benzylcarbamate (0.98 g, 1.48 mmol) in CH2Cl2 (15 mL) was added TFA (2.28 mL, 29.6 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer (clear solution) was washed with brine, dried over MgSO4 and concentrated to give white solid (0.65 g, 70%). 1H NMR (DMSO-d6): δ 8.50 (bs, 1H), 7.52 (s, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.2.9 (d, J=2.8 Hz, 1H), 7.26-7.21 (m, 4H), 7.12-7.08 (m, 3H), 6.97-6.94 (m, 2H), 6.80 (d, J=6.8 Hz, 2H), 4.41 (s, 2H), 4.32 (s, 2H), 3.94 (s, 2H); MS (ESI): (M+H)+=561.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[C:4]([C:22](=[O:23])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1cc(OC)c(C(=O)Cc2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized by reacting methyl 3,5-dimethoxybenzoate with phenylacetyl chloride via the Friedel-Crafts reaction, followed by saponification of the ester obtained, according to the method described in 2.1. It is used in crude form in the following reaction.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=4[CH:17]=[C:16]([C:26]4[O:30][CH:29]=[N:28][C:27]=4[C:31]([OH:33])=O)[CH2:15][N:14]3[C:34]=2[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:36]1([C:12]2[C:11]3[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:35][C:34]=3[N:14]3[CH2:15][C:16]([C:26]4[O:30][CH:29]=[N:28][C:27]=4[C:31]([N:64]4[CH2:69][CH2:68][O:67][CH2:66][CH2:65]4)=[O:33])=[CH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=4[C:13]=23)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: C1COCCN1
Reactant: COc1ccc2c(c1)C=C(c1ocnc1C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Yield: 109 %

Procedure:
5-(10-(tert-Butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylic acid (185 mg, 0.334 mmol) was dissolved in DMF (3.2 ml), and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (193 mg, 0.600 mmol) was added. The reaction was stirred capped at room temperature for 25 minutes and DMAP (163 mg, 1.334 mmol) was dissolved in the reaction then morpholine (0.058 ml, 0.667 mmol) was added. The reaction was capped and stirred at room temperature overnight. The reaction was poured into 30 ml of water and extracted with dichloromethane. The organic layer was washed sequentially with 0.1M aqueous citric acid, 0.1M aqueous NaH2PO4, then dried over anhydrous sodium sulfate. The sample was filtered, volatiles removed and the sample dried in vacuuo to obtain 227 mg of an amorphous orange solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16-1.50 (m, 7H) 1.53-1.61 (m, 6H) 1.62 (s, 10H) 1.76 (d, J=10.38 Hz, 2H) 1.83-2.15 (m, 5H) 3.40-3.84 (m, 7H) 3.83-3.95 (m, 5H) 4.40 (d, J=11.60 Hz, 1H) 5.64 (d, J=12.21 Hz, 1H) 6.97 (d, J=2.75 Hz, 1H) 7.05 (dd, J=8.39, 2.59 Hz, 1H) 7.50 (d, J=8.55 Hz, 1H) 7.53 (s, 1H) 7.65 (d, J=8.24 Hz, 1H) 7.77-7.86 (m, 2H) 7.97-8.04 (m, 1H) 8.10 (s, 1H). LC-MS retention time 2.64 min m/z 624 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:9]([N:16]=[C:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.C(OCC)(=O)C>[CH2:9]([NH:16][C:17](=[O:18])[NH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(N)CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)O)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of 3-amino-3-methylbutanoic acid (5.86 g, 34.2 mmol) in THF was added benzyl isocyanate (5.87 ml, 47.5 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). Then the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (eluent: chloroform:methanol=95:5) to obtain the title compound (5.73 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:9][OH:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:11][C:12]([F:14])([F:15])[F:13])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1cnn2C(CO)(CC(F)(F)F)c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc2c1cnn2C(C=O)(CC(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step B (200 mg, 0.42 mmol) in DCM (5 mL) was added Dess-Martin periodinane (350 mg, 0.84 mmol) in portion at room temperature. The mixture was stirred at for 0.5 h, and then diluted with water (5 mL), extracted with ethyl acetate. The organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/PE=1:8) to afford the title compound. LC/MS m/z=468.2[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:28]3[CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24][C:23]=3[C:22]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[N:21]2)[CH2:13][CH2:12]1.C(O)(=O)C>CCO.[Zn]>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]3[C:28]4[CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:24][C:23]=4[C:22]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=4)=[N:21]3)[CH2:13][CH2:12]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a stirred solution of 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.153 g, 0.244 mmol) in EtOH (2.44 mL) was added zinc dust (0.80 mg, 1.22 mmol) and slow addition of acetic acid (0.70 mL). After 15 min the yellow solution became colorless and the access zinc dust was filtered through a plug of celite. The filtrate was concentrated and the residue was purified by column chromatography (silica, 0-10% MeOH/CH2Cl2) to afford 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine (0.146 g, 100%). MS (electrospray): exact mass calculated for C27H32CIF3N6O2S, 596.2; m/z found, 597.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 6.88 (t, J=8.2 Hz, 1H), 6.63 (t, J=7.6 Hz, 2H), 4.55 (s, 2H), 4.36 (s, 2H), 4.15 (t, J=6.5 Hz, 2H), 3.60-3.70 (m, 4H), 2.97 (t, J=5.3 Hz, 2H), 2.90 (s, 3H), 2.83 (d, J=10.8 Hz, 2H), 2.74 (d, J=11.5 Hz, 2H), 2.37 (t, J=6.6 Hz, 2H), 2.11-2.20 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[O:8][CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]([C:28]([O:30]C)=[O:29])[C:24]([O:26]C)=[O:25])[C:20]#[C:21][CH3:22])=[CH:15][CH:14]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].O.Cl>C(#N)C.[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[O:8][CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]([C:24]([OH:26])=[O:25])[C:28]([OH:30])=[O:29])[C:20]#[C:21][CH3:22])=[CH:15][CH:14]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#CC(c1ccc(NC(=O)C(C)Oc2cccc(C(C)(C)C)c2)cc1)C(C(=O)OC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC#CC(c1ccc(NC(=O)C(C)Oc2cccc(C(C)(C)C)c2)cc1)C(C(=O)O)C(=O)O

Procedure:
A solution of 323 mg (0.67 mmol) of dimethyl 2-(1-{4-[2-(3-tert-butylphenoxy)-propionylamino]phenyl}but-2-ynyl)malonate in 7 ml of acetonitrile and 6.7 ml of 1 N sodium hydroxide solution (aq) was stirred at room temperature for 18 h. The reaction mixture was admixed with water and adjusted to pH=1 with 1 N HCl (aq) and then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. This gave 304 mg of 2-(1-{4-[2-(3-tert-butylphenoxy)propionylamino]phenyl}but-2-ynyl)malonic acid in quantitative yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[O:1]=[CH:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(O)CCOCCOCCOCCO
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=CCOCCOCCOCCC(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 6 g (21.55 mmol) of commercially available 3-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}propanoic acid under standard conditions, first by esterification with benzyl chloride and caesium carbonate and subsequent oxidation with sulphur trioxide-pyridine complex.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1.OO.C(O)(=[O:33])C>>[CH3:1][S:2]([CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)=[O:33]
Reactant: CSCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CC(=O)O
Agent: OO
Product: CS(=O)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 63 from 4'-[(2-methylthiomethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and hydrogen peroxide/acetic acid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]1)=[O:19])[CH2:12][CH2:11][CH2:10]2>>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][C:29]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)=[O:19])[CH2:12][CH2:11][CH2:10]2
Reactant: C[C@H](C(=O)N1CCN(c2ccccc2)CC1)N1CCCc2cc(F)ccc21
Reactant: O=S(=O)(O)Cl
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)N1CCCc2cc(F)ccc21
Temperature: 25 °C

Procedure:
After cooling chlorosulfonic acid (5.5 ml, 3 eq) to 0° C. under N2, (R)-2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperazin-1-yl)propan-1-one (1 g, 2.72 mmol) was added and then allowed to warm up to rt. The solution was poured into an ice-water mixture (250 ml), followed by an extraction with CH2Cl2 (3×100 mL). The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was used without further purification for next step. LCAMS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=466.3; tR=3.49 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=S)([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][C:23]2[NH:24][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:3])[CH3:2])=[N:13][C:14]=2[CH:15]=1)=[O:18]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc2[nH]c(Nc3ccccc3C(C)C)nc2c1

Procedure:
1-Isopropyl-2-isothiocyanatobenzene (5 mmol) and methyl 3,4-diaminobenzoate (5 mmol) were reacted, following general procedure B, to yield 2-(2-Isopropylphenylamino)-1H-benzimidazole-5-carboxylic acid methyl ester, which was purified by silica gel chromatography using DCM/ethyl acetate as eluent.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:23])=O>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]=[CH:10][N:9]=[C:8]2[Cl:23])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6,7-diacetoxy-4(3H)-quinazolinone, 12 (3.20 g, 11.42 mmol) in CHCl3 (60 ml) was added oxalyl chloride (2.2 ml, 17.3 mmol) dropwise at 0° C. The resulting reaction mixture was stirred at room temperature for 15 minutes then was gradually heated to reflux for 5 h during which time the starting material was consumed. The reaction mixture was cooled to 10° C. and the solution was quenched with aq sodium bicarbonate. The organic layer was separated and washed with brine then dried over Na2SO4 and directly taken to the next step without concentration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:9]=3)=[CH:6][CH:7]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)cc1OC
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.9 mmol), 3,4-Dimethoxyphenylboronic acid (0.276 g, 1.5 mmol), Na2CO3 (2 M, 2.5 mL), and Pd(PPh3)2Cl2 (87 mg, 0.7 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give 6-(3′,4′-Dimethoxy-biphenyl-4-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 68% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:21]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([CH3:33])OS1(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[N:14]([C@H:31]([CH3:33])[CH2:32][NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cccnc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 1 intermediate a), from 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O.O>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
A stirred solution of di-tert-butyl malonate (1.5 mL, 6.70 mmol) in N, N-dimethylformamide (15 mL) at 0° C. under argon was treated portionwise over 10 minutes with sodium hydride (276 mg of 60% oil dispersion, 6.90 mmol) and stirred at 0° C. for 15 minutes before allowing to warm to room temperature over 1 hour. A white precipitate was produced. The stirred mixture was cooled to 0° C. and treated with a solution of 4-fluoro-3-nitrotoluene (1.0 g, 6.45 mmol) in N,N-dimethylformamide (2 mL) and a deep purple colour was immediately formed. This mixture was stirred at room temperature for 28 hours then heated at 70° C. for 6 hours. The mixture was cooled, then diluted with water (100 mL) and extracted with Et2O (2×50 mL). The combined extract was washed with water (70 mL), dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (40 g) eluting with toluene to afford the title compound as a yellow oil (660 mg, 29%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[C:5]([OH:7])=[O:6])[N:20]=1
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)O)cs1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 18.6 %

Procedure:
To a solution of 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (20 g) in tetrahydrofuran (50 ml) was added a solution of thiourea (3.9 g) and sodium acetate (4.2 g) in water (50 ml), and the mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure to half of the original volume, which was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate and then washed with ethyl acetate. After the aqueous solution was further adjusted to pH 2.0 with 10% hydrochloric acid, the water was removed by decantation. The residual substance was dissolved in tetrahydrofuran (200 ml), followed by drying over magnesium sulfate. Removal of the solvent gave an oil, which was triturated with diisopropyl ether to give 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetic acid (syn isomer) (3.5 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.CCN(CC)CC.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[Cl:38])[C:32]([N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1)=[O:33]
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (10.4 g; 0.04 mole in 150 ml CH2Cl2) and 6.7 ml Et3N (0.048 mole) was slowly added a solution of 3,4-dichlorobenzoyl chloride (10.05 g; 0.048 mole in 60 ml CH2Cl2). This was stirred at room temperature for 15 minutes.