Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[F:10][C:9]([F:12])([F:11])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2[C@@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-(bromomethyl)-2-(trifluoromethyl)benzene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (87%) as a colorless solid: mp 137-138° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 7.72 (d, J=7.6 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.13 (m, 3H), 7.07-7.00 (m, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q, 2JC-F=30.8 Hz), 127.6, 126.8, 126.4 (q, 5JC-F=5.8 Hz), 124.4 (q, 1JC-F=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1). Anal. Calcd. for C26H18F3NO4: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.16; H, 4.11; N, 3.07.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35])#[N:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:29]#[N:30])[CH:32]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C#N)c2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 17D (1.38 g, 4.38 mmol) in anhydrous dichloromethane (25 mL) was added triethylamine (0.9 mL) followed by 3-cyanobenzoyl chloride (0.727 g, 4.38 mmol) and the mixture was stirred for 4 hours at room temperature. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (50 mL) and H2O (20 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers dried (Na2SO4), filtered, and concentrated to an oil which was chromatographed on a Biotage 40M eluting with 10% hexane/90% ethyl acetate to provide the titled compound. MS (ESI) m/e 445 (M+H)+, 443 (M−H)−; 1H NMR (300 MHz, CD3OD) δ ppm 1.39 (s, 6 H) 1.45 (s, 3 H) 1.65 (m, 1 H) 2.53 (m, 2 H) 3.05 (m, 1 H) 3.19 (m, 2 H) 3.46 (m, 2 H) 3.78 (m, 2 H) 4.61 (m, 3 H) 7.66 (t, 1 H) 7.89 (d, 1 H) 8.11 (d, 1 H) 8.17 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH3:2]>C(Cl)(Cl)Cl.CO>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:15][CH2:16][CH3:17])=[O:12])[CH:7]=[CH:6][C:5]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(CCC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCC(NC(=O)Cc1ccc(CCC(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 5 by alkaline saponification of ethyl 3-[2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-phenyl]-propionate and subsequent purification by column chromatography (chloroform/methanol=9/1).
Reaction SMILES: N=O.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]#[N:17])[N:11]=1)[C:4]([NH2:6])=[NH:5].[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>>[CH:9]1[S:8][C:7]([NH:3][C:4]([NH2:6])=[NH:5])=[N:11][C:10]=1[CH2:12][S:13][CH2:14][CH2:15][C:16]([NH:21][S:18]([NH2:22])(=[O:20])=[O:19])=[NH:17]
Reactant: N#CCCSCc1csc(NC(=N)N)n1
Reactant: NS(N)(=O)=O
Agent: N=O
Product: N=C(N)Nc1nc(CSCCC(=N)NS(N)(=O)=O)cs1
Yield: 78.8 %

Procedure:
An inproved method is disclosed in the European Patent Application No. 128,736 of the same company, where the chromatographic purification could be avoided only by preparing and using an iminoether base of substantially higher purity. From 3-(2-guanidino-thiazol-4-yl-methylthio)-propionitrile solid iminoether base was prepared with a yield of 78.8%, which was reacted with 2.2 molar equivalents of sulfamide in a methanolic medium, at 20° to 30° C. for three days. The crude product obtained with a yield of 62% was recrystallized from aqueous dimethyl formamide, and the obtained material was again precipitated with a base, after dissolution in a mixture of water and acetic acid. The total yield for crude famotidine was accordingly merely 48.8%. The main disadvantage of this process is the high consumption of sulfamide, the many and cumbersome steps involved in the process and that it is very time consuming.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6](=[O:20])[C:5]2=O>O.NN.C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6](=[O:20])[CH2:5]2
Reactant: COc1ccc(CN2C(=O)C(=O)c3cc(F)ccc32)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2C(=O)Cc3cc(F)ccc32)cc1
Yield: 90.3 %

Procedure:
A solution of 5-fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (7.1 g, 24.9 mmol) in hydrazine hydrate (35 mL) and ethanol (15 mL) was refluxed overnight, diluted with water and extracted twice with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate in hexane to afford 6.1 g (90%) of 5-fluoro-1-(4-methoxy-benzyl)-1,3-dihydro-indol-2-one; 1H NMR (CDCl3, 400 MHz) δ 3.59 (s, 2H), 3.77 (s, 3H), 4.83 (s, 2H), 6.63 (dd, 1H, J=4.2, J2=8.6), 6.82-6.91 (m, 3H), 6.96-7.01 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H); HPLC-MS calcd. for C16H14FNO2 (M+H+) 272.1, found 272.3.
Reaction SMILES: [CH2:1]([Si:4]([Cl:7])(Cl)Cl)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:15][C@H:16]([NH:25][CH3:26])[C@@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:1]([Si:4]1([Cl:7])[N:25]([CH3:26])[C@@H:16]([CH3:15])[C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24]1)[CH:2]=[CH2:3]
Reactant: C=CC[Si](Cl)(Cl)Cl
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a cooled (0° C.) solution of allyltrichlorosilane (101 mL, 0.696 mol) in methylene chloride (1.8 L) under argon was added triethylamine (170 mL, 1.21 mol). (1S,2S)-pseudoephedrine (100 g, 0.605 mol) was then added portionwise over 30 min, to maintain internal temperature below 15° C. After the addition was complete the mixture was stirred for 12 hours at ambient temperature. The methylene chloride was removed by distillation and the residue was diluted with pentane (1.5 L). The mixture was vigorously stirred for 12 hours to ensure complete precipitation of the triethylamine salts. Filtration of the resulting suspension through a pad of celite and concentration of the filtrate by distillation afforded the crude product as a pale yellow oil. Purification by distillation under reduced pressure (bp˜120 C, 5 mm Hg) provided 149 g (92%) of (4S, 5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine as a ˜2:1 mixture of diastereomers.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([Li])CCC.[CH3:29][S:30]S(C)(=O)=O.Cl>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]([S:30][CH3:29])[CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: CSS(C)(=O)=O
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Reaction time: 0.67 h
Yield: 42.2 %

Procedure:
In 10 ml of a mixture of anhydrous tetrahydrofuran-hexamethylphosphoric acid triamide (7:3) was dissolved 1.00 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. To the resulting solution was added 10 ml of a tetrahydrofuran solution of 1,1,1,3, 3,3-hexamethylsilazane lithium salt consisting of 1.17 g of 1,1,1,3,3,3-hexamethylsilazane and 6.6 millimoles of n-butyllithium at -78° C., and the resulting mixture was stirred for 40 minutes, after which 500 mg of methyl methanethiolsulfate was added at the same temperature and the mixture was stirred for 15 minutes. Subsequently, the temperature of the reaction mixture was elevated to room temperature. The reaction mixture was introduced into 80 ml of 2N hydrochloric acid with ice-cooling and the resulting mixture was extracted with two 40-ml portions of ethyl acetate. The extracts were combined and washed with water and saturated aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the oily product obtained was purified by a column chromatography (eluant: toluene:ethyl acetate=50:1) to obtain 480 mg (yield: 39.6%) of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]([N:16]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[CH:7]=1
Reactant: COC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(Br)c1Cl
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)cc(Br)c1Cl
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
A stirred solution of tert-butyl methyl (5-bromo-4-chloro-1,3-phenylene)dicarbamate (710 mg, 1.870 mmol) in DMF (10 mL) was treated with NaHMDS (3.93 mL, 3.93 mmol) at 0° C. dropwise. The reaction mixture was stirred for 15 min, and 1-(chloromethyl)-4-methoxybenzene (0.533 mL, 3.93 mmol) was added. The reaction was stirred for 45 min, then heated at 75° C. for 1.5 h. The reaction was quenched with half saturated NH4Cl solution and extracted with EtOAc 3×. The organic layers were combined, dried over Mg2SO4, filtered and concentrated. The crude material was purified by flash column chromatography, eluting with 0%-40% EtOAc/Hex. The desired fractions were concentrated to yield tert-butyl methyl (5-bromo-4-chloro-1,3-phenylene)bis(4-methoxybenzylcarbamate) (953.4 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[CH:6][CH:7]=1.CC([O-])=O.[Na+].[N:28]#[C:29]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:29]#[N:28])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: Cc1cccnc1CN(CCCCN)Cc1ncccc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccnc1CN(CCCCNC#N)Cc1ncccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
To a 0° C. solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-butane-1,4-diamine (237 mg, 0.80 mmol) in MeOH (10 mL) was added NaOAc (200 mg, 2.39 mmol) and cyanogen bromide (94 mg, 1.03 mmol) and stirred at room temperature for 17 hours. Water (10 mL) was added and the reaction mixture was extracted with CH2Cl2 (4×40 mL). The extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to provide pure COMPOUND 198 as a beige solid (190 mg, 74%). 1H NMR (CDCl3) δ 1.45-1.51 (m, 2H), 1.65-1.63 (m, 2H), 2.12 (s, 6H), 2.61-2.65 (m, 2H), 2.83-2.89 (m, 2H), 3.68 (s, 4H), 7.08 (dd, 2H, J=4.2, 7.8 Hz), 7.38 (d, 2H, J=7.8 Hz), 7.57 (br s, 1H), 8.37 (d, 2H, J=4.2 Hz). 3C NMR (CDCl3) δ 18.5, 21.1, 28.3, 44.4, 53.6, 58.2, 118.9, 122.9, 133.4, 138.6, 146.6, 156.7. ES-MS m/z 324 (M+H). Anal. Calcd. for C19H25N5.0.4 CH2Cl2O.0.1CH40: C, 64.95; H, 7.32; N, 19.42. Found: C, 64.65; H, 7.22; N, 19.27.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].Cl[C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.CS(C)=O>O>[Cl:12][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([O:4][CH2:2][CH3:3])[CH:11]=1
Reactant: Clc1cncc(Cl)c1
Reactant: CCO
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cncc(Cl)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium (8.1 g, 338 mmol) was added to ethanol (200 ml). After complete reaction, the excess of ethanol was evaporated. 3,5-Dichloropyridine (40.0 g, 270 mmol) and dimethyl sulfoxide (300 ml) were added to the crude mixture. The mixture was stirred at 70° C. for 1 h. Water (500 ml) was added, followed by extraction twice with ethyl acetate (300 ml). The product was isolated in quantitative yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1)([O-:16])=[O:15].[OH-].[Na+]>CS(C)=O>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][O:1][C:20]2[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCOc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
183 g (1 mol) 1-(2-hydroxyethoxy)-4-nitro-benzene, 173.3 g (1.1 mols) 4-nitrochlorobenzene and 70 g powdered sodium hydroxide were reacted following the procedure described in Example 1 in 600 ml DMSO.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>C(O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: CC(=O)OC1CCc2c(Nc3ccc(C#N)cc3)ncnc21
Yield: 55.2 %

Procedure:
39.3 g of 7-acetoxy-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine [prepared as described in step (b) above] and 24 g of p-aminobenzonitrile were dissolved in 180 ml of ethanol, and the solution was heated under reflux for 1.5 hours. At the end of this time, the solvent was evaporated off under reduced pressure, and the resulting residue was washed with a 1:1 by volume mixture of ethanol and toluene, to give 30 g of the title compound as pale grayish crystals, melting at 215°-217° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([C:17]([F:16])([F:26])[F:27])[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (10 g, 47.6 mmol), 3-trifluoromethylbenzyl chloride (8.33 g, 42.8 mmol), potassium carbonate (13.2 g, 95.1 mmol) and acetonitrile (200 ml) was stirred at 60° C. for 24 hrs. The reaction solution was concentrated under reduced pressure, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:toluene=1:1-1:2-toluene) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-(3-trifluoromethylbenzyl)propionate (10.2 g, 65%) as an oil.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][S:3][S:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(OCC)(=O)C>[CH3:16][S:17]([O:8][CH2:1][CH2:2][S:3][S:4][CH2:5][CH2:6][O:7][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSSCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
10 g of 2,2′-dithiodiethanol and 14.44 g of triethylamine (TEA) are diluted in 100 mL of ethyl acetate (EtOAc). At 0° C., 16.35 g of methanesulfonyl chloride diluted in 35 mL of EtOAc are added dropwise to the reaction medium with rapid stirring. 7.22 g of TEA are introduced and stirring is continued at room temperature for 4 hours 30 minutes. 8.2 g of methanesulfonyl chloride are added dropwise at 15° C. and stirring is continued at room temperature for 17 hours. The precipitate is filtered off and washed with three times 50 mL of EtOAc. The organic phases are extracted with 100 mL of ice-water, 100 mL of water, three times 50 mL of saturated sodium hydrogen carbonate solution (NaHCO3), twice 20 mL of saturated sodium chloride solution (NaCl), and then dried over anhydrous sodium sulfate (Na2SO4). The EtOAc is evaporated off, and 17.49 g of a clear pale yellow oil are collected and stored at −25° C. The analyses indicate that the product is in accordance and pure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: O=C(O)c1cc2ccccc2c(-c2cccc(Cl)c2)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2cccc(Cl)c2)n1
Yield: 71.4 %

Procedure:
Operations are carried out as for Example 7, starting with 1.7 g of 1-(3-chlorophenyl) isoquinoline 3-carboxylic acid, 0.69 g of triethylamine, 0.74 g of ethyl chloroformate and 0.56 g of diethylamine in 60 ml of chloroform. 1.45 g of N,N-diethyl 1-(3-chlorophenyl) isoquinoline 3-carboxamide melting at 116° C., are obtained.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:33])[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[CH:17][C:11]=2[N:10]=1)(C)(C)C.[Li+].[OH-]>CO.O>[Cl:33][C:15]1[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[CH:17][C:11]2[N:10]=[C:9]([S:8][CH2:7][C:6]([OH:34])=[O:5])[NH:13][C:12]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C#Cc3ccc(Oc4ccccc4)cc3)c(Cl)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CSc1nc2cc(C#Cc3ccc(Oc4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of compound 33-1 (29.0 mg, 0.059 mmol) in MeOH (6 mL) was added to 5% aqueous LiOH (3 mL) and the mixture was stirred at rt for 20 h. The mixture was then diluted with water (2 mL), evaporated to ½ of the initial volume and acidified with 5% aqueous HCl. The solution was extracted with EtOAc (3 mL then 1 mL, twice). The organic layers were combined, washed with water (three times, 1 mL) and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1.0 mL), filtered and purified by reverse-phase HPLC to give the title compound as off-white solid. LR-MS (API-ES): calculated for C23H15ClN2O3S 434.1, observed m/e 435.0 (M+H)+ (Rt 2.96 min).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.CN(C)CC(O)=O.[CH3:38][S:39]([O-:41])=[O:40].[Na+]>[Cu]I.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([S:39]([CH3:38])(=[O:41])=[O:40])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: CS(=O)[O-]
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1n[nH]c2cc(Cl)ncc12

Procedure:
6-Chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 13B; 1.0 g, 1.917 mmol), N,N-dimethylglycine (39.5 mg, 0.383 mmol), copper(I) iodide (36.5 mg, 0.192 mmol), and sodium methanesulfinate (276 mg, 2.300 mmol) were combined in a 20 mL microwave tube, evacuated under N2 and charged with DMSO (7.7 mL). The reaction was degassed via vacuum under nitrogen (×3) and irradiated in a microwave reactor to 110° C. for 90 min. The crude reaction mixture was poured into water and filtered. The precipitate was purified by flash chromatography (10-50% EtOAc/DCM) to afford 6-chloro-3-(methylsulfonyl)-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. For C7H6ClN3O2S [M+1]+ 232. found 232.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10](I)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:11]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2-c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(-c3ccnc(Cl)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 50 %

Procedure:
A suspension of 1-(2-chloro-4-pyridyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.95 g, 0.00256 mol) in dimethoxyethane (30 mL) and water (60 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (1.14 g, 0.00281 mol), sodium carbonate (0.68 g, 0.00640 mol) and tetrakis (triphenylphosphine)palladium (0) (0.30 g, 0.00026 mol) at 80° C. for 3 days. The solid was filtered and washed with water. The solid was triturated with ethyl acetate (75 mL) for 6 hours and filtered, washing with ethyl acetate (20 mL). The solid was then triturated with methanol (75 mL) for 6 hours and filtered, washing with methanol (20 mL). The solid was dried in vacuo to give crude N2-{4-[4-amino-1-(2-chloro-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.672 g, 0.00128 mol) as a tan solid: