Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:28]=3)[CH2:12]1)[C:8](=[O:41])[NH:7]2)=[O:5])C.CO.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(Cl)Cl.O>[CH3:34][O:33][C:31]1[N:30]=[C:29]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:28]=[C:27]([O:26][CH:11]2[CH2:10][CH:9]3[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]4[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]3=[O:41])[CH2:23]4)[CH2:12]2)[CH:32]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(OC)nc(-c4ccccc4)n3)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Temperature: 60 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
Compound 7d (362 mg, 0.644 mmol) was dissolved in a 2:1:1 mixture of THF:MeOH:H2O (100 ml). LiOH (1 M, 6.5 ml) was added and the reaction mixture was stirred at 60° C. for 72 h. The reaction mixture was acidified by addition of 5% citric acid whereafter DCM was added. The organic layer was separated, dried (MgSO4), filtered and evaporated which gave the title compound (344 mg, 100%), MS (M+H)+535.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([N:53]([CH2:56][CH3:57])[CH2:54][CH3:55])=[O:52])[CH2:42][CH2:41]1.BrCCCCCC(N(CC)CC)=O.O1C2(CCNCC2)OCC1>O>[CH2:56]([N:53]([CH2:54][CH3:55])[C:51](=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:13]([C:9]2[CH:10]=[N:11][C:12]3[C:7]([C:8]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:30][CH2:31]4)=[O:24])=[CH:21][CH:22]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])=[O:15])[CH2:41][CH2:42]1)[CH3:57]
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Reactant: CCN(CC)C(=O)CCCCCN1CCC(N)CC1
Agent: C1CC2(CCN1)OCCO2
Agent: CCN(CC)C(=O)CCCCCBr
Solvent: O
Product: CCN(CC)C(=O)CCCCCN1CCC(NC(=O)c2cnc3c(OC)cccc3c2Nc2ccc(C(=O)NC3CCN(Cc4ccccc4)CC3)cc2)CC1

Procedure:
N-[1-[6-(Diethylamino)-6-oxohexyl]-4-piperidinyl]-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]-phenyl]amino]-3-quinolinecarboxamide was prepared as a hygroscopic solid (1.14 hydrate) by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]-carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 4-amino-N,N-diethylol-piperidinehexanamide as described for Example 17, Step 5. 4-amino-N,N-diethyl-1-piperidinehexanamide can be prepared from 6-bromo-N,N-diethylhexanamide (Step 1) and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 115°-120° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.49 (s, 1 H), 8.77 (s, 1 H), 8.39 (d, J=7.5 Hz, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 7.69 (d, J=8.7 Hz, 2 H), 7.56 (d, J=1 H) 7.40 (m, 1 H), 7.1-7.3 (m, 6 H), 6.87 (d, J=8.68 Hz, 2 H), 3.95 (s, 3 H), 3.7 (m, 1 H), 3.1-3.6 (m, 7 H), 2.6-2.9 (m, 4 H), 2.1-2.3 (m, 4 H), 1.98 (t, J=11.0 Hz, 2 H), 1.65-1.85 (m, 4 H), 1,1-1.6 (m, 12 H), 0.95-1.1 (doft, J=7.1Hz, 6H); Karl Fischer, 2.63% H2O
Reaction SMILES: C(CC[C:6]1[CH:7]=[C:8](/[C:12](/[CH:37]=[CH:38]/[C:39]2[C:40]([CH3:57])([CH3:56])[C:41]3[C:42]([N:55]=2)=[N+:43]([CH2:48][CH2:49][CH2:50][S:51]([O-:54])(=[O:53])=[O:52])[CH:44]=[C:45]([Cl:47])[CH:46]=3)=[CH:13]\[CH:14]=[C:15]2\[N:16]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[C:17]3[C:22]([C:23]\2([CH3:25])[CH3:24])=[CH:21][C:20]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:19][CH:18]=3)[CH:9]=[CH:10][CH:11]=1)(O)=O.[Na+:58].[Na+].[C:60](C1C=CC(B(O)O)=CC=1)([OH:62])=[O:61]>>[C:60]([C:11]1[CH:6]=[CH:7][C:8](/[C:12](/[CH:37]=[CH:38]/[C:39]2[C:40]([CH3:57])([CH3:56])[C:41]3[C:42]([N:55]=2)=[N+:43]([CH2:48][CH2:49][CH2:50][S:51]([O-:54])(=[O:52])=[O:53])[CH:44]=[C:45]([Cl:47])[CH:46]=3)=[CH:13]\[CH:14]=[C:15]2\[N:16]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:34])=[O:35])[C:17]3[C:22]([C:23]\2([CH3:25])[CH3:24])=[CH:21][C:20]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:19][CH:18]=3)=[CH:9][CH:10]=1)([OH:62])=[O:61].[Na+:58].[Na+:58]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCC(=O)O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccc(C(=O)O)cc2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 15 is prepared analogously to compound 10 (Example 10), except that 4-carboxyphenylboronic acid is used as a starting material. λMeOH=680 nm.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.[OH-].[Na+]>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc2cccnc2c2ncccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
In 3.0 ml of acetic acid was dissolved 1.37 g (5.8 mmol) of 5-nitro-1,10-phenanthroline. A solution prepared by dissolving 1.08 g (4.8 mmol) of stannic chloride (II) dihydrate in 2.2 ml of concentrated hydrochloric acid was added dropwise thereto, followed by stirring at 100° C. for 2 hours. The reaction mixture was made alkaline with a NaOH aqueous solution and extracted with chloroform. After chloroform was distilled off under reduced pressure, a yellow solid was obtained. This was recrystallized from tetrahydrofurane-hexane to obtain 0.75 g (66%) of the desired 5-amino-1,10-phenanthroline (Compound (2)).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[N:18]=1.O>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19](=[O:27])[N:18]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1nc(Cl)c2ccccc2[nH]1
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CCOc2nc(=O)[nH]c3ccccc23)cc1

Procedure:
2-(4-tert-butylphenyl)ethanol (0.3 g, 1.68 mmol) is dissolved in dry tetrahydrofuran (7 ml) and to it is added sodium hydride (48.5 mg, 2.02 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloro-2-quinazolone (0.302 g, 1.68 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: COC([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])=O.[OH-].[K+]>CO>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:27]
Reactant: COC(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 95 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
8.01 gram (15.2 mmol) of (−)-2-methoxycarbonylamino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-2b-1)) was dissolved in 304 ml of methanol. To the solution, 152 ml of 40 percent aqueous solution of potassium hydroxide was added dropwise over 30 minutes and then stirred at 95° C. for 2 hours. The resultant mixture was extracted with 300 ml of ethyl acetate, and the extract was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the residue was purified using a silica gel column chromatography (eluent: ethyl acetate) to obtain 7.16 gram of the titled compound.
Reaction SMILES: N1C=CC=C(C)C=1.C(O)(=O)[C:9](O)=[O:10].[CH2:14]([O:21][NH:22][C@H:23]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:32]([O:31][C:29]([C@@H:26]1[CH2:25][CH2:24][C@@H:23]2[CH2:28][N:27]1[C:9](=[O:10])[N:22]2[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:30])[CH3:33]
Reactant: O=C(O)C(=O)O
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccnc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C

Procedure:
3-picoline (52.6 ml, 543 mmol, 4 eq) was added to a slurry of ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (50 g, 136 mmol, 1 eq) in dichloromethane (1000 ml) at 0° C., followed by a solution of triphosgene (36.4 g, 122.4 mmol, 0.9 eq) in dichloromethane (200 ml). The mixture was stirred at 0° C. until the reaction was deemed to be complete. The reaction was quenched with a solution of sodium bicarbonate (28.6 g, 340 mmol, 2.5 eq) in water (300 ml), and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic layers were washed with water. The organic layer was concentrated in vacuo to give (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester as a solution in dichloromethane (solution yield: 35 g, 116 mmol, 85%). Acetonitrile was added and the solution was concentrated in vacuo to give (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester as a solution in acetonitrile. This solution was diluted with acetonitrile to 700 ml. To this was added ammonium carbamate (11.3 g, 145 mmol, 1.25 eq) and Novozyme 435 (35 g, immobilized Candida antarctica lipase B). The mixture was stirred at 40° C. until the reaction was deemed to be complete. The reaction mixture was filtered and concentrated in vacuo. The solution was diluted with dichloromethane, washed with aqueous ammonium chloride, and concentrated in vacuo. Chlorobutane was added and the solution was concentrated in vacuo. The precipitate was isolated by filtration, washed with chlorobutane and dried to give 2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide as a white solid (24.3 g, 88 mmol, 65% from ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate).
Reaction SMILES: C(=[N:14][C:15]1[N:16]=[C:17]2[CH:23]=[C:22]([CH3:24])[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]2=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].NO.Cl>CO>[CH3:24][C:22]1[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:18]2=[N:19][CH:20]=[C:15]([NH2:14])[N:16]=[C:17]2[CH:23]=1
Reactant: Cc1cc2nc(N=C(c3ccccc3)c3ccccc3)cnc2n1COCC[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: Cc1cc2nc(N)cnc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Benzhydrylidene-[6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine (0.158 g, 0.357 mmol), NaOAc (70 mg, 0.857 mmol) and NH2OH HCl (45 mg, 0.643 mmol) were dissolved in MeOH (4 mL) and stirred at RT overnight, and partitioned between EtOAc and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (24 g SiO2, hexanes/EtOAc 0-90% EtOAc) to give 58 mg of 6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine as a yellow solid (58% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=[O:12].[CH:13]#[CH:14]>>[C:13]([C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][CH:2]=1)[C:5](=[O:12])[O:6][C:7]2=[O:11])#[C:14][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=[O:12]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: C#C
Product: O=C1OC(=O)c2cc(C#Cc3ccc4c(c3)C(=O)OC4=O)ccc21

Procedure:
According to an aspect of the invention, a 5-haloisobenzofuran-1,3-dione, such as 5-bromoisobenzofuran-1,3-dione, is reacted with ethyne to obtain 5,5′-(ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:9]1=[O:26].[ClH:27].C(OCC)C>C(OCC)(=O)C>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(c3ccccc3F)C2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1N(c2ccccc2F)CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52 %

Procedure:
tert-Butyl 4-(3-(2-fluorophenyl)-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (235 mg, 0.647 mmol) was dissolved in ethyl acetate (3.0 mL). 2N Hydrogen chloride in diethyl ether (5.0 mL, 10.00 mmol) was added to the mixture. Reaction stirred at room temperature for 22 hours. Solids were filtered off, washed with diethyl ether and then dried in vacuo. Title compound was obtained as white solid in 52% yield. MS (M+H)+=264.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:31]=2[N:32]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1.FC(F)(F)C([O-])=O>>[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[S:29][C:30]=2[CH:36]=1
Reactant: COC(=O)C(CCN(C)C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Agent: O=C([O-])C(F)(F)F
Product: CN(C)CCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1)C(=O)O
Yield: 16.3 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-[2-(dimethyl-amino)ethyl]-4-oxobutanoate (60 mg, 0.17 mmol) and 2,6-dichloro-1,3-benzothiazole (51.8 mg, 0.25 mmol)) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 14.1 mg (13%) of the desired product as the trifluoroacetate salt. 1H NMR (400 MHz, CD3OD) δ 8.10 (d, 2H), 7.70-8.10 (m, 8H), 7.30 (m, 1H), 3.60 (m, 1H), 3.30-3.40 (m, 3H), 3.10 (m, 1H), 2.95 (s, 6H), 2.20 (m, 1H), 2.00 (m, 1H). LC-MS m/z 508.1 (MH+), ret. time 2.66 min.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[CH:15]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:4]([O:6][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:21]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:22])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: O=C(OCCCCCl)C1CCCCC1
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Product: COC(=O)/C=C/C(=O)OCCCCOC(=O)C1CCCCC1
Yield: 50 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (1.00 g, 7.68 mmol) was reacted with CsHCO3 (2.22 g, 11.52 mmol) and chlorobutyl cyclohexanecarboxylate (2.16 g, 9.98 mmol) at ca. 55° C. to afford 1.2 g (50% yield) of the title compound (44) as a clear oil after purification by mass-guided preparatory. HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.90-6.77 (m, 3H), 3.81 (s, 3H), 2.34-2.28 (m, 1H), 1.91-1.88 (m, 2H), 1.82-1.73 (m, 4H), 1.65-1.62 (m, 2H), 1.47-1.39 (m, 4H), 1.29-1.23 (m, 2H), 0.98-0.94 (t, 3H). MS (ESI): m/z 313.09 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:46])[C@H:14]([CH3:45])[NH:15][C:16](=[O:44])[C@H:17]([CH3:43])[NH:18][C:19](=[O:42])[C@H:20]([CH3:41])[NH:21][C:22](=[O:40])[C@@H:23]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CCO.O>[OH:2][CH2:1][C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:46])[C@H:14]([CH3:45])[NH:15][C:16](=[O:44])[C@H:17]([CH3:43])[NH:18][C:19](=[O:42])[C@H:20]([CH3:41])[NH:21][C:22](=[O:40])[C@@H:23]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[N:5][CH:4]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(CO)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following the procedure as described in Example 32, except using the material from Example 75 (106 mg, 0.119 mmol), EtOH/H2O (4:1) (4 mL), sodium borohydride (32.7 mg, 0.864 mmol) and stirring at room temp for 1 h, the title compound is isolated (quantitative yield) that is used crude in the next step. LC/MS (Condition A): ret. T=2.51 min, (M+H)+ 664.46.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]1=[O:17].[Br-].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][Zn+])[CH3:25].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:4]([CH2:5][CH:6]2[CH2:10][CH2:9][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7]2=[O:17])[C:3]=1[F:22])[CH3:25]
Reactant: CCOC(=O)CCC[Zn+]
Reactant: O=C1C(Cc2c(Cl)ccc(Br)c2F)CCN1C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1F
Yield: 90.7 %

Procedure:
Dissolve 3-(3-bromo-6-chloro-2-fluoro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 30) (1 g, 2.6 mmol) and Pd(dppf)Cl2 (80 mg, 0.1 mol) in THF (degassed, 40 mL) and add 4-ethoxy-4-oxo-butylzinc bromide (15 mL, 7.7 mmol, 0.5 M THF solution). Reflux the reaction for 3 hours. Add the reaction mixture into ice and water. Extract the mixture with ethyl acetate (100 mL). Wash the organic layer with brine (50 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure. Purify the residue by column chromatography using 10% EA/H to 30% EA/H to obtain the title compound (1 g, 92%) as yellow oil: Mass spectrum (ion spray): m/z=424.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN(C)C=O>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[O:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:20][CH2:21]1
Reactant: Clc1nc2ccccc2s1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4nc5ccccc5s4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred mixture of 5.5 parts of 4-[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-ylamino]-1-piperidineethanol and 135 parts of N,N-dimethylformamide were added 0.75 parts of a sodium hydride dispersion 50%. After stirring for 30 minutes at room temperature, 2.54 parts of 2-chlorobenzothiazole were added and the whole was further stirred for 3 hours. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.6 parts (61%) of N-[1-[2-(2-benzothiazolyloxy)ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine; mp. 147.0° C. (compound 67).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccccc2F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccccc1-c1cccc(CBr)c1
Yield: 81.7 %

Procedure:
A mixture of 2'-fluoro-3-methyl[1,1'-biphenyl] (1.1 g, 0.006 mole) and N-bromosuccinimide (1.1 g, 0.006 mole) in 11 ml of carbon tetrachloride was irradiated with white light to afford 3-bromomethyl-2'-fluoro[1,1'-biphenyl] (1.3 g). The nmr spectrum was consistent with that expected for the named compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1I)[C:6]#[N:7])#[N:2].C[S-:13].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[SH:13])[C:6]#[N:7])#[N:2]
Reactant: N#Cc1ccc(I)c(C#N)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(S)c(C#N)c1
Temperature: 80 °C
Yield: 81 %

Procedure:
Under argon, 3.03 g (12.10-3 mol) of 3-cyano-4-iodobenzonitrile and 3.36 g (48.10-3 mol) of sodium thiomethylate are dissolved in 80 ml of anhydrous hexamethylphosphoramide and the solution obtained is then heated at 80° C. for 45 minutes. The resulting reaction medium is hydrolyzed in an ice/1N HCl mixture and then extracted with methylene chloride. The organic phase is washed with water and then dried over magnesium sulfate and evaporated under reduced pressure to give 1.55 g (yield: 81%) of the expected product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH2:15][CH3:16])=[CH:7][C:6]=1[CH3:17]>CO.[Pd]>[NH2:11][C:9]1[C:8]([O:14][CH2:15][CH3:16])=[CH:7][C:6]([CH3:17])=[C:5]([NH:4][CH2:3][CH2:2][OH:1])[CH:10]=1
Reactant: CCOc1cc(C)c(NCCO)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(C)c(NCCO)cc1N
Yield: 75.4 %

Procedure:
644 mg (2.7 mmol) of 2-(2'-hydroxyethyl)amino-5-ethoxy-4-nitrotoluene were hydrogenated with a catalytic amount of palladium/active carbon (5% Pd) in 50 ml methanol. After filtering off the catalyst, the solvent was completely distilled away. 428 mg (76% of theoretical yield) of 4-amino-2-(2'-hydroxyethyl)amino-5-ethoxytoluene were obtained in pure form by thin layer chromatography. The obtained product crystals melted at 128° C.