Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([O:25][CH3:26])=[CH:13][C:12]=2[CH:27]=[O:28])=[C:7]([O:29][CH3:30])[CH:6]=1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[CH2:18]([O:17][C:15]1[C:14]([O:25][CH3:26])=[CH:13][C:12]([CH:27]=[O:28])=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[O:29][CH3:30])[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2cc(OCc3ccccc3)c(OC)cc2C=O)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(-c2ccc(C(=O)O)cc2OC)cc1OCc1ccccc1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
A solution of 5′-benzyloxy-2′-formyl-2,4′-dimethoxy-biphenyl-4-carboxylic acid methyl ester (5.7 g, 14 mmol) and Lithium hydroxide (0.6 g, 26 mmol) in THF/water(1:1, 30 mL) was stirred overnight at room temperature. Additional Lithium hydroxide (0.2 g, 8.8 mmol) was added and stirring was continued for another 3 h. The reaction mixture was acidified with 2 M hydrochloric acid (500 mL) to pH=4, extracted with ethyl acetate (2×100 mL) and then dichloromethane (50 mL). The organic phases were combined, washed with saturated aqueous ammonium chloride followed by drying and concentration under reduced pressure. Crystallization of the residue from dichloromethane/hexane provided 5′-benzyloxy-2′-formyl-2,4′-dimethoxy-biphenyl-4-carboxylic acid (3.1 g, 57%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.[N:18]1([C:23](=N)[NH2:24])C=CC=N1.CCOCC>CN(C=O)C>[OH:7][C@H:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:23]([NH2:24])=[NH:18])[CH2:3]1
Reactant: N=C(N)n1cccn1
Reactant: N[C@H]1CC[C@H](O)C1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N[C@H]1CC[C@H](O)C1
Reaction time: 0.17 h
Yield: 164.8 %

Procedure:
To a stirred solution of (1S,3S)-3-aminocyclopentanol (9.00 g, 89.0 mmol) (obtained from ASID pharmaceuticals) in DMF (45 mL) at RT under nitrogen was added DIPEA (31.0 mL, 178 mmol) followed by 1H-pyrazole-1-carboximidamide hydrochloride (14.7 g, 133 mmol). After stirring overnight Et2O (150 mL) was added and the reaction was stirred for 10 min. The Et2O was decanted and concentrated under high vacuum to afford 21 g (99%) of 1-((1S,3S)-3-hydroxycyclopentyl)guanidine (164) as a dark orange oil: MS m/z (APCI-pos) M+1=144.1
Reaction SMILES: [OH-].[Al+3].[Li+].[OH-].[OH-].[OH-].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]([CH3:18])[O:13][C:14]2=[O:15])=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]([OH:13])[CH3:18])=[C:16]([CH2:14][OH:15])[CH:17]=1
Reactant: CC1OC(=O)c2cc(Br)ccc21
Agent: [Al+3]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)cc1CO
Reaction time: 2 h
Yield: 99.3 %

Procedure:
18.30 g of lithium aluminium hydroxide was suspended in 1.0 l of THF, to which 300 ml of THF solution of 36.44 g of 6-bromo-3-methylphtalide (3-5) was dropped at −30° C. and the resulting mixture was stirred at the same temperature for 2 hours. After the reaction was completed, 76 ml of water and 19 ml of 15% sodium hydroxide solution were added thereto, and the resulting residue was separated by filtering and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, which was washed with saturated salt water and dried over anhydrous magnesium sulfate, and thereafter, the solvent was distilled off under reduced pressure to obtain 36.84 g of 1-bromo-4-(1-hydroxyethyl)-3-hydroxymethylbenzene (3-6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][CH:10]=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22]>C(OCC)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][CH:10]([OH:11])[CH2:22][CH:21]=[CH2:20])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OC(CC=O)c1cccc(Br)c1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC(O)CC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of 3-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)propanal (17.9 g, 52.1 mmol) in dry diethyl ether (150 mL) is added 1 M allylmagnesium bromide solution in ether (52.1 mL, 52.1 mmol). The resulting mixture is warmed to room temperature over 1 hour. The mixture is diluted with dichloromethane and is quenched by addition of saturated aqueous solution of ammonium chloride. The mixture is extracted three times with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a racemic diastereomeric mixture (18.8 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.38-7.34 (m, 1H), 7.24-7.21 (m, 1H), 7.19-7.15 (m, 1H), 5.84-5.76 (m, 1H), 5.09-5.04 (m, 1H), 5.00 (t, J=5.3 Hz, 1H), 4.86-4.80 (m, 1H), 3.83-3.75 (m, 2H), 2.23-2.15 (m, 2H), 1.80-1.69 (m, 2H), 0.89 (d, 9H, J=6.6 Hz), 0.06-0.04 (m, 3H), −0.17 (d, J=40.4 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:10](Br)[CH2:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH2:3]1.[CH:12]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18]O)([CH3:14])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[CH:12]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][O:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)NCC(O)CO
Reactant: O=C1Cc2scnc2CC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)NCC(O)COc1ccc2ncsc2c1
Reaction time: 49 h
Yield: 57 %

Procedure:
A mixture of 6-oxo-5-bromo-4,5,6,7-tetrahydrobenzothiazole (100 parts), 3-isopropylamino-1,2-propanediol (67 parts), p-toluenesulfonic acid monohydrate (99 parts) and toluene (1550 parts) is heated under reflux for 21 hours while drying the refluxing azeotropic mixture according to the method described in Example I. After cooling, the reaction mixture is adjusted to pH 9 by adding aqueous 2.5N-sodium hydroxide and formed organic layer is separated. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining 4'-isopropylaminomethyl-5-bromo-4,5,6,7-tetrahydrobenzothiazole-6-spiro-2'-[1,3]-dioxolane (156 parts) is dissolved in piperidine (1560 parts), and stirred for 49 hours on an oil bath heated at 95° to 100° C. The reaction mixture is concentrated under reduced pressure to leave residue which is mixed with ethyl acetate and water, shaken and fractionated to separate formed organic layer. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue (172 parts) is recrystallized from ethanol-hydrochloric acid giving 6-(3-isopropylamino-2-hydroxypropoxy)benzothiazole (65 parts) in 57% yield. mp. 132°-134° C. (hydrochloride trihydrate).
Reaction SMILES: C12(COC3C(Cl)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][C:37]=3[C:45]([F:48])([F:47])[F:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.[N:49]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]OC[CH2:50]1.N1(S(N)(=O)=O)CCC1>>[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH:58][S:55]([N:49]4[CH2:54][CH2:53][CH2:50]4)(=[O:57])=[O:56])=[O:42])=[CH:38][C:37]=3[C:45]([F:47])([F:48])[F:46])[CH2:25][CH:26]3[CH2:32][CH:30]([CH2:29][CH:28]([CH2:27]3)[CH2:33]1)[CH2:31]2
Reactant: O=C(O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1
Reactant: NS(=O)(=O)N1CCOCC1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1

Procedure:
Following the procedure as described in Example 98 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoic acid and morpholine-4-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.05 g, 22%): 1H NMR (300 MHz, DMSO-d6) 11.92 (s, 1H), 8.26-8.22 (m, 2H), 7.38-7.35 (m, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.76 (s, 2H), 2.20-2.09 (m, 2H), 1.99 (br s, 3H), 1.75-1.63 (m, 12H); MS (ES−) m/z 471.3 (M−1); MS (ES+) m/z 473.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([C:8]1[N:12]2[CH:13]=[C:14](F)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:7].[NH2:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([OH:29])[CH2:21][CH2:20]1.[H-].[Na+].N>CN(C=O)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([C:8]1[N:12]2[CH:13]=[C:14]([O:29][C@H:22]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([NH2:18])[CH2:20][CH2:21]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH3:7]
Reactant: CN1CCC[C@@]1(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC[C@@]1(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
To a solution of Intermediate 47b (150 mg, 0.64 mmol) and Intermediate A (126 mg, 0.64 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 90 mg, 2.24 mmol) portionwise. The mixture was stirred at 60° C. for 1.5 h then allowed to cool to RT. The mixture was carefully quenched by pouring into MeOH (10 mL), then applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a brown solid (180 mg, 75%). LCMS (Method 4): Rt 0.49, m/z 378 [MH+].
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:27]C)=[CH:10][C:11]([O:25]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:13]3=[O:24])[CH2:6][CH2:5][N:4]1[CH3:29].Cl.N1C=CC=CC=1>>[OH:25][C:11]1[CH:10]=[C:9]([OH:27])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:29])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:24])[CH:14]=[C:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:16]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4)oc23)[C@@H]1CO

Procedure:
Compound of example 56 (0.5 g, 1.27 mmol) was treated with dry pyridine hydrochloride (5 g, 43.29 mmol) as described in the example 17, to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].[S-:20][C:21]#[N:22].[K+].BrBr>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]=[C:21]([NH2:22])[S:20][C:18]=2[CH:19]=1)[CH3:11]
Reactant: Cc1ccc(F)c(C(C)Oc2ccc(N)cc2)c1F
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: Cc1ccc(F)c(C(C)Oc2ccc3nc(N)sc3c2)c1F
Yield: 98.6 %

Procedure:
6-[1-(2,6-Difluoro-3-methylphenyl)ethoxy]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 3.5 g of 4-[1-(2,6-difluoro-3-methylphenyl)ethoxy]aniline, 5.2 g of potassium thiocyanate and 0.681 cm3 of dibromine. We obtain 4.2 g of 6-[1-(2,6-difluoro-3-methylphenyl)ethoxy]-1,3-benzothiazol-2-amine in the form of a brown-coloured solid, which has the following characteristics:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]([F:59])([F:58])[C:32]([O:50][Si:51]([CH2:56][CH3:57])([CH2:54][CH3:55])[CH2:52][CH3:53])([C:46]([F:49])([F:48])[F:47])/[CH:33]=[CH:34]\[CH2:35][C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]/[CH2:42]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:59][C:31]([F:30])([F:58])[C:32]([O:50][Si:51]([CH2:56][CH3:57])([CH2:54][CH3:55])[CH2:52][CH3:53])([C:46]([F:48])([F:49])[F:47])/[CH:33]=[CH:34]\[CH2:35][C:36]([CH3:44])([CH3:45])[CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]/[CH2:42][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2s1
Reactant: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CO)(C(F)(F)F)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CSc1nc2ccccc2s1)(C(F)(F)F)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 6.59 g of 2-mercapto-benzothiazole and 7.87 g of triphenylphosphine in 65 ml of THF was added at 0° a solution of 9.25 g of (2E,9Z)-12,12,12-Trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-dien-1-ol in 35 ml of THF which was followed by addition of 8.09 g of diisopropyl azodicarboxylate over 20 min and stirring was continued at 0° for 1 h after which time t.l.c. indicated completion of the reaction. The mixture was washed with sat. aqueous NH4Cl- and NaCl-solution, the organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica with hexane/AcOEt 9:1 to give 11.13 g of the pure (t.l.c.) title compound as a yellow oil. IR (neat): 1663w (C═C). MS (EI): 611/7 (M).
Reaction SMILES: CN(C)[C:3](=[O:6])[CH2:4][CH3:5].O=P(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]([CH3:26])[CH:22]=[CH:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]([CH3:26])[C:22]([C:3](=[O:6])[CH2:4][CH3:5])=[CH:23][C:24]=2[CH3:25])=[CH:18][CH:19]=1
Reactant: Cc1ccn(C)c1-c1ccc(Cl)cc1
Reactant: CCC(=O)N(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.8 %

Procedure:
N,N-dimethyl propionamide (3.24 g, 3.52 ml, 32.08 mmol) was cooled at 0-5° C. and and to this was added POCl3 (4.9 g, 2.9 ml, 32.08 mmol) slowly in a dropwise manner. The resulting mixture was then stirred at room temperature (about 25° C.) for 20 minutes. The reaction mixture was then diluted with 1,2-dichloroethane (60 ml) and cooled to 0° C. To the cooled reaction mixture was then added a solution of 2-(4-chlorophenyl)-1,3-dimethyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 6.0 g, 29.17 mmol) in 1,2-dichloroethane (60 ml) dropwise. The reaction mixture was then heated to reflux for 30 minutes. The progress of the reaction was monitored by TLC. The mixture so obtained was allowed to cool to room temperature and was diluted with aqueous solution of sodium acetate trihydrate (21.8 g, 160.4 mmol in 45 ml water). The mixture so obtained was further heated to reflux for 30 minutes, two layers were separated. The aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layer was washed with water (1×100 ml) and dried over anhydrous Na2SO4. The solvent from the reaction mixture was evaporated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 4-6% ethyl acetate in hexanes as an eluent to obtain the title compound (6.55 g, 85.8%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[OH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)=[CH:44][CH:43]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(N5CCC(O)CC5)cc4)nc23)CC1)Nc1nccs1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.060 g, 0.15 mmol, 1 eq), EtOH (2.6 mL) and DMF (0.35 mL), 4-(4-hydroxypiperidin-1-yl)benzaldehyde (0.034 g, 0.17 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aq NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.011 g, 13%); 1H-NMR (500 Mz, DMSO-d6): 1.40-1.50 (m, 2H), 1.77-1.87 (m, 2H), 2.60-2.92 (br s, 4H, piperazine N(CH2)2), 2.95-3.05 (m, 2H), 3.63-3.85 (m, 7H), 4.61-4.75 (br s, 1H, CHOH), 7.04 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.24-7.29 (m, 1H) and 7.50 (d, J=3.5 Hz, 1H) thiazole H-4, H-5), 8.01 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.07 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 3.69 min—514/516 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[C:13]4[C:18]([CH2:19][C:7]=3[C:6]=2[CH:5]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4.[CH3:20]I>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[CH3:20][N:9]1[C:10]2[CH:11]=[CH:12][C:4]([CH3:3])=[CH:5][C:6]=2[C:7]2[CH2:19][C:18]3[C:13]([C:8]1=2)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CI
Reactant: Cc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C)-c2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 100 mL of 50% aqueous NaOH solution is added 0.5 gram of trimethylcetylammonium bromide, 6.1 grams of 8-methyl-5, 10-dihydroindeno[1,2-b]indole, and then 100 mL of toluene with vigorous stirring. Methyl iodide (1.8 mL) is then added. The mixture is stirred for three hours at 25° C. and then heated at 100° C. for 30 minutes. After cooling to 25° C., two layers are formed: a pale yellow organic layer and an aqueous layer. They are separated. The precipitate in the organic layer is filtered. The aqueous layer is extracted with toluene, which is then combined with the organic layer, the mixture is then dried over Na2SO4, and filtered. The resulting solution is concentrated till a solid is formed. The solid is isolated from the solution, and combined with the previously collected solid product. The combined solid is washed with ethanol and then with hexane and dried, yielding 3.05 grams of 5,8-dimethyl-5,10-dihydroindeno[1,2-b]indole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:31][C@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][CH2:34][OH:35]>C1COCC1>[OH:35][CH2:34][CH2:33][C@H:32]([NH:31][C:13]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:12][CH2:11][S:10]1)=[O:15])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCSC1C(=O)N[C@@H](CCO)c1ccccc1
Temperature: -25 °C

Procedure:
Commercial 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid (III) (1 g, 4.29 mmol) was dissolved in dry THF (50 ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. The solution was cooled down to −25° C. and N-methyl morpholine (1.084 g, 10.72 mmol) was added in dry THF (5 ml). A solution of isobutyl-chloroformate (0.615 g, 4.5 mmol) in dry THF (10 ml) was then added dropwise over a period of 10 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of −25° C. by the use of a dry-acetone bath. After the complete addition of the chloroformate, the reaction mixture was stirred at −25° C. for 30 min after which time an amine (IV)/(IV*), e.g., (3S)-3-amino-3-phenyl-1-propanol (0.778 g, 5.14 mmol) was added drop-wise over a period of 10 min. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The solvent was removed and the residue re-dissolved in ethyl acetate (150 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). Organics then dried with magnesium sulfate and concentrated in vacuo. The product (V), e.g., tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, was finally obtained as a white foam (1.5 g, 95%). The antipodal intermediate, tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, as well as the racemic inter-mediate, tert-butyl 2-({[3-hydroxy-1-phenylpropyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate were made according to the same protocol, starting from commercial (3R)-3-amino-3-phenylpropan-1-ol or 3-amino-3-phenylpropan-1-ol, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C.N[C:17]1[C:21]([C:22]#[N:23])=C[NH:19][N:18]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:19]2[N:18]=[CH:17][C:21]([C:22]#[N:23])=[C:14]2[N:12]=[CH:11][CH:10]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cnn2c(-c3cc(Cl)ccc3Cl)ccnc12
Yield: 92.5 %

Procedure:
A mixture of 98.3 g of 2',5'-dichloro-3-dimethylaminoacrylophenone and 43.5 g of 3-aminopyrazole-4-carbonitrile in one liter of glacial acetic acid was heated at reflux for 63/4 hours. The reaction mixture was cooled and diluted with water to provide a precipitate which was collected, washed with water and dried in vacuo to give 107.6 g of 7-(2,5-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as pale yellow crystals, mp 202°-204° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[O:26])[CH:20]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:32]1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: C1CCNC1
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CCCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and pyrrolidine. LCMS (M+H)+: m/z=513.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](I)[CH:27]=[C:26]([CH3:31])[N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:28]2[CH:27]=[C:26]([CH3:31])[N:25]=[C:24]([F:23])[CH:29]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc(F)n1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc(F)n1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-fluoro-4-iodo-6-picoline (CAS RN: [884494-45-5]) was prepared the title compound as a colorless oil, MS (EI): m/z=411 ([M]+, 1Br).