Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([NH:29][CH3:30])[CH:26]([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:30])(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CNCC(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)CN(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (82 mg, 0.22 mmol), isobutyl(methyl)amine (38 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) in MeCN (4 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 54 mg (58% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.91 (d, J=6.64 Hz, 6 H), 1.46-1.61 (m, 4 H), 1.64 (s, 9 H), 1.82-1.95 (m, 1 H), 2.25-2.45 (m, 1 H), 2.69 (s, 3 H), 2.74 (d, J=7.42 Hz, 2 H), 3.29-3.40 (m, 2 H), 3.87-4.00 (m, 2 H), 4.49 (d, J=7.42 Hz, 2 H), 7.82 (dd, J=8.69, 1.66 Hz, 1 H), 7.98 (d, J=8.79 Hz, 1 H), 8.08 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=422.0; Anal. Calcd for C22H35N3O3S+0.90 TFA+0.20 EtOAc (541.85): C, 54.53; H, 6.98; N, 7.75. Found: C, 54.53; H, 6.99; N, 7.77.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21](O)=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl-].C[N:26](C=O)C>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([NH2:26])=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Reactant: CN(C)C=O
Agent: [Cl-]
Solvent: ClCCl
Product: NC(=O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(isoquinolin-5-yl)-1-naphthoic acid (0.86 mg, 0.29 mmol) was suspended in CH2Cl2 (2 mL) and oxallyl chloride (0.038 mL, 0.4 mmol) was added followed by a drop of DMF. Mixture was stirred at room temperature for 3 h and solvent was evaporated and residue dried under vacuum. The crude acid chloride was dissolved in a solution of NH3 in dioxane and was stirred at room temperature. Solvent was evaporated, a solution of aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 and then with ethyl acetate. Residue was purified by prep plate (5% MeOH/CH2Cl2) to give the title compound as a solid. MS (ESI pos. ion) m/z: 299. (M+H). Calc'd Exact Mass for C20H14N2O: 298.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C(N(CC)CC)C.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1>CN(C)C=O>[Cl:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NCc4cccc(Cl)c4)cc1c23
Yield: 69.2 %

Procedure:
To the title compound of Example 7 (hydrochloride) (40 mg, 0.13 mmol), and triethylamine (0.053 mL, 0.38 mmol) in N,N-dimethylformamide (0.9 mL) was added 1-bromomethyl-3-chloro-benzene (0.17 mL, 0.13 mmol) dropwise with stirring. After stirring overnight, the mixture was chromatographed on silica eluting with 2:1 hexane:ethyl acetate to afford, after isolation, the title compound (36 mg, 0.090 mmol) as a yellow powder in 71% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:10][C:9]2=[N:11][C:12]([CH2:14][CH3:15])=[CH:13][C:8]2=[C:7]([Cl:16])[N:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>O1CCCC1.C(Cl)Cl>[CH3:3][S:4][C:5]1[N:6]=[C:7]([Cl:16])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=3)[C:9]=2[N:10]=1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a suspension of 48 mg (2.00 mmol) of sodium hydride in 4.0 mL of tetrahydrofuran was added 227 mg (1.00 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine and 410 mg (2.00 mmol) of 3-chlorobenzyl bromide. The reaction was stirred at ambient temperature for 18 hours then diluted with 30 mL of methylene chloride and washed with 20 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (25 g silica, methylene chloride-heptane gradient 1:1 to 100:0) to provide 350 mg (99%) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.33 (t, J=7.4 Hz, 3H), 2.58 (s, 3H), 2.59 (q, J=7.4 Hz, 2H), 5.30 (s, 2H), 6.29 (s, 1H), 6.92 (d, J=7.4 Hz, 1H), 7.09 (s, 1H), 7.23 (m, 2H)
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)Cl.[CH:6]1([Li])[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl-].[Li+]>CCCCC.CCOCC>[CH:6]1([Si:2]([CH:9]2[CH:8]=[CH:7][CH:6]=[CH:10]2)([Cl:5])[Cl:1])[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: [Li]C1C=CC=C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCC
Solvent: CCOCC
Product: Cl[Si](Cl)(C1C=CC=C1)C1C=CC=C1
Reaction time: 0.17 h

Procedure:
50 ml of dry n-pentane, 20 ml of dry ether and 8.09 g (47.6 mmol) of tetrachlorosilane were charged in a 200 ml Schlenk tube reactor equipped with a stirring apparatus in a stream of nitrogen, and a liquid having 7.20 g (100 mmol) of the above prepared cyclopentadienyl lithium slurried with 70 ml of n-pentane was dropwise added thereto by means of an injector at room temperature over a period of 10 minutes. After completion of the dropwise addition, stirring was carried out at room temperature for 24 hours. After completion of the reaction, lithium chloride was removed from the reaction liquid slurry by means of a glass filter, and n-pentane was distilled off to obtain dicyclopentadienyldichlorosilane.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([Cl:33])[N:4]=1.[CH3:34][O-:35].[Na+]>C1COCC1.O>[Cl:33][C:5]1[N:4]=[C:3]([CH2:2][O:35][CH3:34])[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CBr)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (from the synthesis of Intermediate 11B/Step 2; 64 mg, 0.123 mmol) was dissolved in THF (1.5 mL), charged with sodium methoxide (0.080 mL, 0.370 mmol, 4.6 M), and allowed to stir at room temperature for 30 min. The reaction mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-50% EtOAc/hexanes) to give 6-chloro-3-methoxy-4-(methoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. For C28H24ClN3O2 [M+1]+ 470. found 470.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[O:6])[CH3:2].CO[CH:10]=[CH:11][C:12](=[CH2:18])[O:13][Si](C)(C)C>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]([CH:5]1[CH2:18][C:12](=[O:13])[CH:11]=[CH:10][O:6]1)=[O:7])[CH3:2]
Reactant: CCOC(=O)C=O
Reactant: C=C(C=COC)O[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CCOC(=O)C1CC(=O)C=CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A solution of glyoxylic acid ethyl ester, polymer form (2.02 g, 8.9 mmol) and (3-methoxy-1 methylene-allyloxy)trimethylsilane (1.9 ml, 8.9 mmol, Danishefsky's diene) in benzene (12 ml) was placed under nitrogen. Zinc chloride (0.5 N in tetrahydrofuran, 8.9 ml, 4.45 mmol) was added and the reaction stirred at ambient temperature for 72 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate (100 ml) and washed with 1 N hydrochloric acid (20 ml), saturated sodium bicarbonate (20 ml), and brine (20 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of ethyl acetate/hexane (1:2) as eluent. Pure fractions were collected and the solvent evaporated in vacuo which afforded 1.2 g (75%) of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][C:16]([O:18]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8]C(OCC)=O.[H-].[Na+].C(O)C.Cl>C1(C)C(C)=CC=CC=1>[N:1]12[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][C:16](=[O:18])[CH2:15][CH2:14]2
Reactant: CCOC(=O)CCC1CCCCN1CCC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: O=C1CCC2CCCCN2CC1
Yield: 80.9 %

Procedure:
A solution of diethyl piperidine-1,2-dipropionate (9.60 g, 0.034 mole) in xylene (100 ml) was added dropwise over 4 h to a flask containing 250 ml of xylene, which was being fed via a continuous extraction apparatus to a stirred, refluxing, suspension of sodium hydride (4.2 g of 80%, 0.14 mole) in xylene (100 ml) containing ethanol (0.5 ml) under nitrogen. The reaction mixture was heated under reflux for a total of 40 h, then cooled in an ice bath and treated with 5M HCl acid (250 ml). The aqueous layer was separated, treated with concentrated HCl acid (30 ml) and heated under reflux for 18 h. The solution was cooled, basified with potassium carbonate and extracted with ether (3×100 ml). The combined extracts were dried (Na2CO3), concentrated in vacuo and the residue distilled in a Kugelr ohr apparatus to give the title compound as a colourless oil (4.6 g, 84%) bp approx. 110° C. at 0.25 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:5]([CH:4]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: BrC/C=C/c1ccccc1
Reactant: COC(=O)/C=C(\C)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)C(C/C=C/c1ccccc1)C(C)=O

Procedure:
Analogously to Example 28A, 10 g (72.4 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate and 0.40 g (2.41 mmol) of potassium iodide are reacted with 14.3 g (72.4 mmol) of [(1E)-3-bromo-1-propenyl]benzene to give methyl (4E)-2-acetyl-5-phenyl-4-pentenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][N:23]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccncn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 4-pyrimidinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.CN1C(=O)CCC1>C(N(CC)CC)C>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:25]=[N:26][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH2:30][C:29]5[CH:36]=[CH:37][CH:38]=[CH:39][C:28]=5[CH3:27])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:15]([CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Reactant: Cc1ccccc1CC1CCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4Cc4ccccc4C)cc2OCC3)n(CC(F)(F)F)n1
Temperature: 160 °C
Yield: 25.2 %

Procedure:
A 10 mL microwave vial was charged with 8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (85 mg, 0.22 mmol) and 2-(2-Methyl-benzyl)-pyrrolidine (231 mg, 6 eq). 0.5 mL of NMP and 0.5 mL of triethylamine was added. The vial was sealed and heated at 160° C. for 24 h. After cooling to room temperature, the solution was purified directly by reverse phase HPLC (0.1% NH4OH/ACN). The isolated solid was further purified by chiral SFC (AD column, 35% MeOH isocratic) to give 27 mg of one enantiomer and 29 mg of 420 (48% total yield). LCMS: 524.2. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 9.08 (s, 1H), 7.92 (s, 1H), 7.27-7.06 (m, 4H), 5.99 (s, 1H), 5.80 (q, J=8.9 Hz, 2H), 4.50 (m, 4H), 4.38 (br s, 1H), 3.49 (t, J=8.6 Hz, 1H), 3.15 (d, J=10.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.10-1.89 (m, 2H), 1.81-1.71 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:45]([O:49][C:50]([NH:52][NH2:53])=[O:51])([CH3:48])([CH3:47])[CH3:46]>CN(C)C=O.O>[C:45]([O:49][C:50]([NH:52][NH:53][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([C:12]2[O:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][N:11]=2)[CH:15]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ccc(-c2cnc(-c3cccc(C(=O)O)c3)o2)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cnc(-c3cccc(C(=O)NNC(=O)OC(C)(C)C)c3)o2)cc1
Reaction time: 48 h
Yield: 78.2 %

Procedure:
1.5 g (5.0 mmol) of 3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoic acid from Preparation 4, 1.3 g (6.6 mmol) EDAC.HCl, 0.89 g (6.6 mmol) HOBT, and 0.87 g (6.6 mmol) hydrazinecarboxylic acid tert-butyl ester was dissolved in 20 mL of dimethylformamide. Stirring was continued 48 hours at room temperature. Water (60 mL) was added, and the product was extracted with 1:1 THF/EtOAc (2×). Combined the organic extracts and washed with saturated aqueous NaCl solution (3×), dried (MgSO4). Dried in a vacuum oven overnight at 70° C. to provide 1.6 g (82%) of desired product. MS: m/z (APCI, AP+) 410 [M−]+
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:23])[CH2:19][CH3:20]
Reactant: CCCN=C=O
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Product: CCCNC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The title compound was prepared from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one (Example 1 (B)) and n-propyl isocyanate according to the procedure of Example 10. The confirmatory elemental analysis for the product, mp 85°-87° C., is shown in Table III.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:20][C:21](=[CH2:24])[CH2:22][NH2:23]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][C:21]([CH3:24])=[CH2:20])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: C=C(C)CN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)CNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In DMF, 700 mg (3.4 mol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and 759 mg (7.5 mmol) of triethylamine was added thereto, followed by adding 404 mg (3.8 mmol) of 2-methyl-2-propenylamine thereto, under ice cooling. The reaction solution was stirred at 0° C. for 1 hour and allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 687 mg (yield: 79.3%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].[C:28]([O:33]C)(=[O:32])[C@H:29]([CH3:31])O.BrBr>C(Cl)(Cl)Cl>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([CH3:31])[C:28]([OH:33])=[O:32]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@H](C)O
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br)C(=O)O

Procedure:
Prepared from of 2,6-dibromo-4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl )-phenol (Example 59) and commercially available (S)-lactic acid, methyl ester. White solid: mp 129-196° C. dec; Opt. rot. [a]25/D=+4.312° (8.812 mg/mL, CHCl3); NMR (DMSO-d6); δ13.12 (broad s, 1 H), 8.12 (d, J=8, 1 Hz, 1 H), 8.06 (d, J =7 Hz, 1 H), 7.82 (q, J=Hz, 2 H), 7.75 (ddd, J=8,7, 1 Hz, 1 H), 7.62-7.49 (m, 3 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.61 (d, J=8 Hz, 1 H), 5.12 (q, J=7 Hz, 1 H), 1.63 (d, J =7 Hz, 3 H); MS (+FAB): [M+], 2 bromine isotope pattern, 680 (45%), 682 (100%), 684 (60%); Anal. Calc. for C25H15Br2IO3S: C, 44.02, H, 2.22, N, 0.00; Found: C, 44.66, H, 2.54, N, 0.21.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([O:10][C:11]([NH:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]([C:30]2[N:31]=[CH:32][N:33]([C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=3)[CH:34]=2)([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>CN(C=O)C>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([N:33]2[CH:34]=[C:30]([C:21]([CH2:20][C:17]3[CH:18]=[N:19][C:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])=[CH:15][CH:16]=3)([C:22]([O:24][CH3:25])=[O:23])[C:26]([O:28][CH3:29])=[O:27])[N:31]=[CH:32]2)=[CH:40][CH:39]=1
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc(N)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
824 mg (3.66 mmol) of tin(II) chloride dihydrate were added to a solution of 384 mg (0.73 mmol) of the compound from example 12e in 10 ml of DMF and stirred at RT overnight. The solvent was then evaporated off, and the residue was partitioned between EA and sat. aqueous NaHCO3 solution. The aqueous phase was extracted twice with EA. The combined organic phases were dried over Na2SO4, filtered and concentrated. 103 mg of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:19])([CH3:18])[CH2:12][C:13](OCC)=[O:14])[NH:8]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][OH:14])[NH:8]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(CCO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: -78 °C
Reaction time: 10 h
Yield: 22.5 %

Procedure:
To a solution of ethyl 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutanoate (34 g, 0.11 mol) in dry CH2Cl2 (400 mL) was added drop-wise DIBAL-H (283.4 mL, 0.27 mol) over 2 hours at −78° C. The reaction mixture was stirred for 10 hours at −78° C. and then quenched by adding water (200 mL). The precipitate was filtered off and washed with methanol. The filtrate was extracted with CH2Cl2 (200 mL×3), the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-methylbutan-1-ol (6.6 g, 22%). 1H NMR (400 MHz, CDCl3) δ 9.35 (brs, 1H), 8.30 (d, J=7.6 Hz, 1H), 7.11 (d, J=12.0 Hz, 1H), 6.35 (d, J=1.2 Hz, 1H), 3.74 (t, J=6.4 Hz, 2H), 1.9 (t, J=6.4 Hz, 2H), 1.4 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([S:33]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CNS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
To a stirring solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.00 g, 9.0 mmol) and triethylamine (1.32 mL, 9.45 mmol) in dry tetrahydrofuran (25.5 mL) at 0° C. was slowly added a solution of m-nitrobenzenesulfonyl chloride (2.09 g, 9.45 mmol) in tetrahydrofuran (7.3 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq) and layers separated. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (4.0 g, 100%). LCMS for C18H21N3O6S (M-Boc+H)+: m/z=308.0. 1H NMR (400 MHz, CD3OD): δ 8.43 (t, J=2.0 Hz, 1H), 8.31 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.04 (dt, J=8.0, 2.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.19 (br, 1H), 7.04 (m, 2H), 6.77 (dt, J=7.2, 1.2 Hz, 1H), 4.13 (s, 2H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.