Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:19])[CH2:5][C:6]([C:8]2[C:16]3[O:15][C:14]([F:18])([F:17])[O:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:19])[C:5](=[CH:22][N:23]([CH3:25])[CH3:24])[C:6]([C:8]2[C:16]3[O:15][C:14]([F:18])([F:17])[O:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(CC(=O)C1CC1)c1cccc2c1OC(F)(F)O2
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1cccc2c1OC(F)(F)O2)C(=O)C1CC1
Reaction time: 8 h

Procedure:
A solution of 4-(3-cyclopropyl-1,3-dioxoprop-1-yl)-2,2-difluoro-1,3-benzodioxole (12.0 g) in dry toluene was treated with N,N-dimethylformamide dimethyl acetal and the mixture stirred overnight. After evaporation in vacuo and re-evaporation after addition of toluene the residue was recrystal from cyclohexane-ethanol to give 4-(3-cyclopropyl-2-dimethylaminomethylene-1,3-dioxopropyl)-2,2-difluoro-1,3-benzodioxole (6.5 g) as a pale yellow solid, m.p. 118°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:27])=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].[BH4-].[Na+].CCCCCC.CCOC(C)=O.Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:27])=[CH:8][C:9]=1[N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][CH2:16]1)[C:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of 5-Bromo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (5.9 g, 12.9 mmol) in 50 ml of MeOH under a positive N2 add NaBH4 (250 mg, 6.4 mmol, 0.5 eq.) portion wise (approx. 30 minutes). After the addition is completed, check for reaction completion by TLC Hexane:EtOAc 1:1). Add 10 ml of HCl 2% and stirred for 15 min. The reaction mixture was concentrated under vacuum to dryness. The reaction mixture was recuperated with water (25 ml) and extracted with EtOAC. The organic phases were combined and dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel column chromatography using EtOAc:hexanes as eluent to obtain 5-Bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (4.5 g, 77% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(C1C=NC2C(C=1)=CC=C(OC1C3C(=CC(OCC4CCN(C)CC4)=C(OC)C=3)N=CN=1)C=2)#N>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:13](=[O:12])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][NH:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: COc1cc2c(Oc3ccc4cc(C#N)cnc4c3)ncnc2cc1OCC1CCN(C)CC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(OC)ccc2c1=O
Temperature: 240 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
m-Anisidine (50 g, 407 mmol) and diethyl ethoxymethylenemalonate (102 g, 407 mmol) were heated at 60° C. for 20 minutes. Diphenyl ether (270 ml) was then added and the temperature was raised to 240° C. over 30 minutes. The ethanol formed distilled off. Heating was maintained at this temperature for 1 hour then the reaction mixture was allowed to cool to 120° C. at which point the reaction mixture was diluted with heptane and allowed to stand overnight at ambient temperature. The brown solid was collected by filtration and washed with methanol and ether to give ethyl 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (45 g, 45%). This reaction was repeated twice.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:25]=1
Reactant: Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: O=Cc1cccnc1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NCc4cccnc4)c3)n2)cc1

Procedure:
Intermediate 24 was coupled with pyridine 3-carboxaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 398. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.6 (s, 1H), 8.4 (d, 1H) 8.2 (d, 1H) 7.8 (d, 1H), 7.4-7.3 (m, 3H), 7.2 (t, 1H), 7.1 (d, 2H), 6.9 (d, 2H), 6.8 (d, 1H), 6.7 (d, 1H), δ 4.4 (s, 2H), δ 3.6 (t, 2H), 2.8 (t, 2H).
Reaction SMILES: C(C1C=C(NC(=O)C2C=CC(C3CCNCC3)=CC=2)C=CC=1)(C)(C)C.Cl[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=1.[C:36]([C:40]1[CH:41]=[C:42]([NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([N:55]3[CH2:60][CH2:59][N:58](C4C=CC(C(O)=O)=CC=4)[CH2:57][CH2:56]3)=[C:51](F)[CH:50]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:41]=[C:42]([NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([N:55]3[CH2:60][CH2:59][N:58]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=4)[CH2:57][CH2:56]3)=[CH:51][CH:50]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cn4)CC3)cc2)c1

Procedure:
6-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 6-chloro-nicotinic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H31N3O3 (m/e) 457, obsd 458 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CN(C=[O:17])C>>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][OH:17])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CN(C)C=O
Product: CCOP(=O)(CCCO)OCC

Procedure:
Diethyl-3-hydroxypropylphosphonate (steps 1 and 2) is prepared from diethyl-3-bromopropylphosphonate. Diethyl-3-bromopropylphosphonate (12.0 g, 46 mmol), prepared by the method of Eberhard, A., et al, J Am Chem Soc (1965) 87:253-260) was stirred with 12.0 g NaOAc.3H2O in 125 ml DMF heated in a steam bath. The reaction was evaporated to dryness in vacuo after 2 hours and partitioned between H2O and EtOAc. extracting the aqueous layer five times. The ethyl acetate extract was washed once with brine, dried with Na2SO4, filtered, and evaporated to dryness in vacuo to yield 9.8 g light yellow oil (89%). 1H NMR (CDCl3) δ1.3 (tr, 6 H), 1.5-2.0 (m, 4 H), 2.03 (s, 3 H), 4.1 (dq, 6 H): thin-layer chromatography on SiGF developed with 2:1 EtOAc:CH2Cl2 gave Rf 0.30. The isolated diethyl-3-acetoxypropylphosphonate (9.8 g, 41 mmol) in 200 ml abs. EtOH was stirred with 30 ml Dowex 50 (H+) which had been rinsed three times each with H2O and EtOH. After 41/2 days at room temperature, another 10 ml of similarly prepared resin was added. Six hours later, the reaction was filtered and evaporated in vacuo. The quantitative yield of yellow oil was purified by dry column chromatography on 400 g silica packed in a 2.75-inch flat diameter nylon tube. The column was eluted with 1:9 MeOH:EtOAc and the appropriate fractions were cut and slurried with 1:1 MeOH:EtOAc. Filtration and evaporation in vacuo afforded 5.33 g (66%) pale yellow oil, which is the diethyl ester of 3-hydroxypropyl phosphonic acid. 1H NMR (CDCl3, D2O): δ1.3 (tr, 6 H), 1.6-2.08 (m, 4 H), 3.67 (tr. 2 H), 4.13 (dq. 4 H); thin-layer chromatography on SiGF developed with 1:9 MeOH:EtOAc gave an Rf of 0.57.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]([O:25][C:26](=[O:39])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]([NH2:38])[C:33]([N:35]([CH3:37])[CH3:36])=[O:34])([CH3:24])([CH3:23])[CH3:22]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:38][C@H:32]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:39])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.73 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 78-2 (6.76 mmol, crude form) as starting materials respectively 0.90 g (Isomer A, colorless amorphous) and 1.69 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])[CH2:6][CH2:5]2)OC1.[ClH:18].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH2:24])=[NH:23]>C(#N)C>[ClH:18].[F:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:20]2[C:21]=1[C:22]([NH2:24])=[N:23][C:4]1([CH2:5][CH2:6][N:7]([C:10]([N:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)=[O:11])[CH2:8][CH2:9]1)[NH:19]2
Reactant: O=C(N1CCCC1)N1CCC2(CC1)OCCO2
Reactant: N=C(N)c1c(N)cccc1F
Agent: Cl
Solvent: CC#N
Product: NC1=NC2(CCN(C(=O)N3CCCC3)CC2)Nc2cccc(F)c21
Yield: 29.9 %

Procedure:
1-(1-pyrrolidinylcarbonyl)-4-piperidone ethylene ketal (120 mg, 0.5 mmol) and 2-amino-6-fluorobenzamidine hydrochloride (113 mg, 0.5 mmol) in dry acetonitrile (10 ml) were heated at reflux for 18 h. The mixture was cooled and filtered and the filtrate treated with an equal volume of dry ether. After standing in the refrigerator overnight the pale yellow solid which separated was filtered, washed with dry ether and dried to give the title compound (55 mg), m.p. 246°-248° C. (dec.).
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([F:31])[CH:16]=2)[CH:10]2[CH2:11][CH:6]3CC(C[CH:4]1[CH2:5]3)C2)#N.C12(COC3C(C4CC4)=CC(C(OC(C)(C)C)=O)=C(F)C=3)CC1CCCC2>>[C:3]12([CH2:13][O:14][C:15]3[C:27]([CH:28]4[CH2:30][CH2:29]4)=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:31])[CH:16]=3)[CH2:1][CH:4]1[CH2:5][CH2:6][CH2:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6 and making non-critical variations to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was obtained as a colorless solid (0.30 g, 37%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.5 Hz, 1H), 6.42 (d, J=12.8 Hz, 1H), 3.61 (d, J=9.1 Hz, 1H), 3.78 (d, J=9.1 Hz, 1H), 1.96-1.52 (m, 7H), 0.92-0.82 (m, 4H), 0.67-0.61 (m, 4H), 0.38-0.33 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>>[ClH:28].[N:25]1[CH:24]=[CH:23][C:22]([S:19]([C:16]2[S:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:18][CH:17]=2)(=[O:20])=[O:21])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(S(=O)(=O)c3ccncc3)s2)CC1
Agent: Cl
Product: O=S(=O)(c1ccncc1)c1cnc(N2CCNCC2)s1
Yield: 99 %

Procedure:
Prepared in analogy to example 4 (d) from 4-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and hydrogen chloride solution. The crude material was purified by recrystallisation from ether to afford the title compound as a light yellow crystalline solid (yield 99%). MS (m/e): 311.0 (M+H+, 100%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[CH:15](=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].O>C1(C)C=CC=CC=1.O1CCCC1>[CH:12]([O:11][C:9]([O:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[CH:15]=[O:23])=[O:10])([CH3:14])[CH3:13]
Reactant: CC(C)OC(=O)Cl
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)Oc1ccccc1C=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
26 ml (190 mmol) of triethylamine and then 185 ml (190 mmol) of a 1M solution of isopropyl chloroformate in toluene are added dropwise to a solution containing 15 g (120 mmol) of salicylaldehyde in 150 ml of tetrahydrofuran at 0° C. The mixture is stirred at 0° C. for 2 hours and then at ambient temperature for 18 hours. Water is added and the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. 27 g of 2-(isopropoxy-carbonyloxy)benzaldehyde are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:19])[C:15]([Cl:18])([Cl:17])[Cl:16].[N+:20]([O-])([OH:22])=[O:21]>C(O)(C)C>[CH3:8][N:9]1[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=[C:10]1[C:14](=[O:19])[C:15]([Cl:16])([Cl:17])[Cl:18]
Reactant: O=[N+]([O-])O
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Temperature: -40 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
An acetic anhydride solution (200 ml) containing 3 (45.2 g, 0.200 mol) was cooled to −40° C., and then fuming nitric acid (18.5 ml, 0.360 mol) was dropped into the solution at the same temperature. After stirring the mixture for 2 hours at a room temperature, isopropanol was added to precipitate a solid. The precipitated solid was collected by filtration to obtain a nitro substance 5 (27.2 g). The filtrate was distilled under a reduced pressure, and the obtained residue was subjected to silica gel column chromatography to further obtain 5 (10.7 g) from an elusion position of ethyl acetate-hexane (1:10, v/v). (Total yield: 70%)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([C:24]([F:27])([F:26])[F:25])=[C:18]3[N:17]([CH2:28][CH3:29])[C:16]2=[O:30])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.CCOC(C)=O>[CH2:28]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[C:24]([F:26])([F:25])[F:27])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:30])[CH3:29]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C(F)(F)F)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Reaction time: 4 h
Yield: 66.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) and 10% palladium on carbon (50% wet, 68 mg) in MeOH (6.5 ml) and EtOAc (6.5 mL) was hydrogenated under balloon pressure at room temperature for 4 h. The solid was filtrated and washed with MeOH (10 ml) to remove the catalyst. The filtrate was concentrated in vacuo to give the title compound (103 mg).
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: CN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a DMSO solution (4 ml) of 200 mg (0.755 mmol) of 6-chloro-7-fluoro-8-nitro-9H-β-carboline was added 1-methylpiperazine (226 mg, 2.26 mmol) and DIEA (400 mg, 3.09 mmol) via a syringe. The reaction was allowed to stir at RT overnight. Upon addition of water, an orange solid precipitated out. The solid was filtered, washed and dried to give 236 mg (91% yield) of the desired 6-chloro-7-(4-methyl-piperazin-1-yl)-8-nitro-9H-β-carboline. 1H-NMR (300 MHz, DMSO-d6): δ 2.24 (s, 3H), 2.48 (m, 4H), 3.13 (m, 4H), 8.13 (d, 1H), 8.40 (d, 1H), 8.73 (s, 1H), 8.94 (s, 1H), 12.05 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.72 min. MS (M+H+): 346.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[C:7]([F:24])[C:6]=1[NH:25][CH:26]1[CH2:28][CH2:27]1)C.[OH-].[Na+]>O1CCCC1.CO>[C:20]([O:19][C:17]([NH:16][CH:13]1[CH2:14][CH2:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([NH:25][CH:26]3[CH2:27][CH2:28]3)[C:7]=2[F:24])[CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)O)c(NC3CC3)c2F)C1
Yield: 112.2 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2-cyclopropylamino-3-fluorobenzoic acid ethyl ester (Example 3j, 1.34 g, 3.29 mmol) and aqueous sodium hydroxide (2N, 20 mL) in tetrahydrofuran (20 mL) and methanol (20 mL) is refluxed for 1 hour. The solution is partially concentrated in vacuo, then acidified to pH 6 and extracted with chloroform. The combined organic extracts are dried over Na2SO4, filtered, and concentrated to give the title compound (1.40 g). 1H NMR (CDCl3): δ 7.59 (dd, 1H), 6.06 (dd, 1H), 4.80–4.70 (bd, 1H), 4.38–4.22 (m, 1H), 3.79–3.50 (m, 3H), 3.47–3.35 (m, 1H), 2.98–2.87 (m, 1H), 2.30–2.14 (m, 1H), 1.97–1.84 (m, 1H), 1.46 (s, 9H), 0.69–0.54 (m, 4H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11].[Br:26][C:27]1[N:32]2[N:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>CC(O)C>[Br:26][C:27]1[N:32]2[N:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:29][CH:28]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CC(C)N1CCC(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1

Procedure:
N,N-Diisopropylethylamine (200 μL, 1.2 mmol) is added to a mixture of 4-(1-isopropylpiperidin-4-yl)phenylamine (220 mg, 1.0 mmol) and 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (280 mg, 1.0 mmol) in iPrOH (5 mL) and heated at reflux for 48 h. The mixture is cooled and the solvent evaporated under reduced pressure to afford an orange-brown solid. This is partitioned between DCM (50 mL) and water (20 mL) and the layers are separated. The organic phase is washed with citric acid (10% aq., 3×25 mL). The combined washings are extracted with DCM (25 mL) and then made basic by addition of NaHCO3 (s). The mixture is extracted with DCM (3×25 mL) and the combined extracts dried over MgSO4 and evaporated. The crude product was purified by chromatography on silica gel, eluting with 5%-10% MeOH in DCM to afford the desired compound, contaminated with the starting aniline. This was recrystallised from MeOH to afford the pure title compound (110 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[O-:29][CH2:30][CH3:31].[Na+]>C(O)C.CO>[CH2:30]([O:29][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1)[CH3:31]
Reactant: CC[O-]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOCc1nc(-c2c(-c3ccccc3)noc2C)cn1-c1ccc([N+](=O)[O-])cc1
Yield: 92 %

Procedure:
As described for Example 150, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol), using sodium ethoxide in ethanol instead of sodium methoxide in methanol, was converted to the title compound (47 mg, 92%) which was obtained as a yellow solid. MS: m/e=405.5 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[O:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: C(=Cc1ccco1)c1ccncc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1cc(CCC2CCCO2)ccn1
Yield: 19.3 %

Procedure:
A solution of 1-(pyridin-4-yl)-2-(furan-2-yl)ethene (15.0 g, 87.7 mmol) [Example 18, Step 1] in methanol (300 ml) was treated with ammonium formate (27.6 g, 438.5 mmol) and 10% palladium on charcoal catalyst (1.5 g, 10% (w/w)). The mixture was stirred at reflux for 3 hours. The catalyst was removed by filtration and the solvent was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed with 1:1 hexane/ethyl acetate as eluant to afford the title compound as a colourless oil (3.0 g, 19%); δH (DMSO-d6) 1.35-1.50 (1H, m, tetrahydrofuranyl H), 1.70-2.00 (5H, m, CH2 and 3×tetrahydrofuranyl H), 2.54-2.76 (2H, m, CH2), 3.54-3.82 (3H, m, tetrahydrofuranyl H), 7.22 (2H, d, J 7.1 Hz, ArH), and 8.46 (2H, d J 7.0 Hz, ArH); m/z (CI+, NH3) 178 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24](O)=[O:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:24]([C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=4)=[O:25])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reactant: Cn1ccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (30 mg, 1.1 eq, 0.13 mmol) was added to a solution 1-methyl-1H-imidazole-2-carboxylic acid (15 mg, 1.0 eq, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 1.1 eq, 0.13 mmol), 1-hydroxybenzotriazole (16 mg, 1.0 eq, 0.12 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a yellow solid (14 mg, 0.04 mmol, 35%). LCMS: [M+H]+=335, Rt=1.44 min, 100% purity.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.Cl.[CH:16]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[CH:16]1([N:24]2[C:2]3[N:7]4[N:8]=[CH:9][N:10]=[C:6]4[N:5]=[C:4]([CH3:11])[C:3]=3[CH2:12][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: NC1CCCCCCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c2c1CCN2C1CCCCCCC1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 1.45g of cyclooctylamine hydrochloride, 4 ml of triethylamine and 20 ml of isopropyl alcohol was stirred under reflux for 1.5 hours, and treated thereafter as described in Example 5. The crystals thus obtained were recrystallized from ethanol to give 1.25g of colorless needles of m.p. 188.5° - 190.5° C.