Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]([CH:7]([CH3:29])[CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]=[C:11]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:6]>CO>[CH3:1][N:2]([CH3:3])[C:5]([CH:7]([CH3:29])[CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]=[C:11]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:6]
Reactant: CNC
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)Cl
Solvent: CO
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 64 h
Yield: 63 %

Procedure:
In an dimethylamine (40% in water, 10 ml) was placed 1-[3-(chlorocarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (600 mg, 1.5 mmol). To this mixture 10 ml of methanol were added, to enhance solubility and the mixture was stirred for about 64 hours at room temperature. The reaction mixture was then concentrated under reduced pressure to produce 600 mg as a tan foam. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions containing the desired material were combined and concentrated in vacuo to yield 375 mg (63%) of the desired title compound as a white foam.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[Br:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:2][CH2:3][CH2:4][O:5][CH3:6])[CH:9]=1
Reactant: COCCCI
Reactant: O=c1cc(Br)cc[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COCCCOc1cc(Br)ccn1
Temperature: 45 °C

Procedure:
11 mmol of silver carbonate and 20 mmol of 1-iodo-3-methoxypropane [61542-10-7] are added under an argon atmosphere to a solution of 21 mmol of 4-bromo-1H-pyridin-2-one [36953-37-4] in 30 ml of benzene. The reaction mixture is heated to 45° C. with exclusion of light for 2 days. The mixture is cooled to room temperature and filtered through Hyflo. The filtercake is washed with benzene and with saturated, aqueous sodium hydrogencarbonate solution. The phases of the filtrate are separated and the aqueous phase is extracted with dichloromethane (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])[C:5](Cl)=[O:6].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([CH2:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[C:2]([Br:1])[CH:3]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCC(C)Cc1ccc(C(=O)Cl)cc1Br
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(Br)c3)cc2)cc1
Reaction time: 2 h

Procedure:
This 3-bromo-4-(2'-methylbutyl)benzoic acid chloride (11.5 g, 0.04 mol) was dropwise added to a mixture of 4-hydroxy-4'-octyloxybiphenyl with anhydrous pyridine under ice cooling, followed by agitating the resulting mixture at 50°-60° C. for 2 hours, adding toluene (100 ml), sufficiently agitating the mixture, washing it with 6N-HCl, then with 2N-NaOH aqueous solution and further with water, further drying over anhydrous MgSO4, distilling off toluene and recrystallizing the residue from a mixture of ethanol (100 ml) with ethyl acetate (60 ml) to obtain 3-bromo-4-(2'-methylbutyl)benzoic acid 4'-octyloxy-4-biphenylyl ester (12.2 g), which exhibited liquid crystalline properties and had the following phase transistion points: ##STR45##
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N:7]1([CH2:12][CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(C1CCCN1)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C1CNC(CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Lithium aluminum hydride (9 g) is suspended in dry tetrahydrofuran (100 ml) under ice-cooling, and thereto is added dropwise a solution of 2-(1-pyrrolidinyl)carbonylpyrrolidine (33 g) in dry tetrahydrofuran (80 ml). The mixture is refluxed under nitrogen atmosphere for four hours. The mixture is cooled with ice, and thereto is added a saturated aqueous sodium sulfate solution (about 15 ml), and then mixture is further stirred at room temperature for three hours. The precipitated sodium sulfate is removed by filtration, washed well with chloroform. The filtrate and the washings are combined, concentrated under reduced pressure, and evaporated to give 2-(1-pyrrolidinyl)methylpyrrolidine (22 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[F:38])[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[N:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C>[CH:32]1([C:30]([NH:29][C:27]2[N:28]=[C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]4[CH:35]=[CH:36][C:37]([F:38])=[C:16]([NH:15][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:10])[CH:17]=4)=[N:25][N:24]3[CH:26]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: Cc1cn(C)nc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cn(C)nc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 63 %

Procedure:
To a suspension of 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (151 mg, 1.08 mmol) in tetrahydrofuran (2.0 mL) were added N,N-dimethylformamide (1 drop) and thionyl chloride (0.08 mL, 1.1 mmol), and the mixture was stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure and dissolved in N,N-dimethylacetamide (2.0 mL). On the other hand, to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol) in N,N-dimethylacetamide (6.0 mL) was added dropwise the above-mentioned solution under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) and recrystallized from tetrahydrofuran/ethanol to give the title compound (283 mg, 63%) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:27][N:26]=4)=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(NC1CCC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccc(-c2ccccc2)cn1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
5-Bromo-pyridine-2-carboxylic acid (4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide (example 30A66, step 1) (80 mg, 0.155 mmol) and phenylboronic acid (27 mg, 0.22 mmol) were dissolved under argon in 0.4 ml 2M sodium carbonate and 1.6 ml 1,2-dimethoxyethane. Triphenylphosphine (16 mg, 0.062 mmol) and Pd(II)acetate (7 mg, 0.03 mmol) were added and the mixture stirred at 85° C. for 16 hrs. The reaction mixture was extracted with water and two times dichloromethane. The organic extracts were washed with water and brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired compound was obtained as a brown solid (36 mg, 45%), MS: m/e=514.1 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: COCCN
Product: COCCNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 was coupled to 2-methoxyethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 18.8 mg of 188. MS (Q1) 439.1 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[NH2:12][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[C:15]([CH2:14][OH:13])[CH:16]=[CH:17][CH:18]=2)[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Product: Cc1cc2nc(N)cc(-c3cccc(CO)c3)n2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J) and 3-(hydroxymethyl)phenylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.40 (s, 3 H), 4.79 (s, 2 H), 4.90 (br, 2 H), 6.03 (s, 1 H), 6.09 (s, 1 H), 7.51-7.54 (m, 2 H), 7.82-7.85 (m, 1 H), 7.94 (s, 1 H).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.O.N1(O)C2C=CC=CC=2N=N1.Cl.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([OH:39])=[O:38].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1F)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1F)c1ccccc1
Yield: 16.3 %

Procedure:
A solution of DCC (534 mg, 0.71 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (217 mg, 1.42 mmol), (2-fluoro-phenylamino)-phenyl-acetic acid hydrochloride (I247) (200 mg, 0.71 mmol) and (R)-quinuclidin-3-ol (271 mg, 2.13 mmol) in THF (10 mL) is stirred at RT for 2 days. The solvent is evaporated and the residue is taken up with EtOAc, washed with sat NaHCO3, water and brine. The organic layer is collected, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by preparative HPLC. The organic solvent is evaporated and the acid aqueous phase is basified with Na2CO3 and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and evaporated to afford the title compound as yellow oil (41 mg, 16% yield).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH3:16])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cc1C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 3,4-dimethylphenylboronic acid (0.333 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.557 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 48 h to give 4-chloro-2-(3,4-dimethylphenyl)-5,7-difluoro-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=318.1 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1S.O>C1COCC1>[CH2:19]([CH:3]([CH2:1][CH3:2])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[S:13][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[CH:9][CH:10]=1)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[CH3:20]
Reactant: CCC(CC)C(c1ccc(N=C=S)cc1)n1cncn1
Reactant: Nc1ccccc1S
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)C(c1ccc(Nc2nc3ccccc3s2)cc1)n1cncn1
Yield: 49.6 %

Procedure:
A mixture of intermediate (19b) (0.1665 mol) and 2 aminobenzenethiol (0.2 mol) in THF (500 ml) was stirred and refluxed overnight. The mixture was cooled, poured out into water, extracted with CH2Cl2 and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone/diethyl ether. The precipitate was filtered off and dried, yielding 31.2 g (49.6%) of (±)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (comp. 25).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>O>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: O
Product: C[C@H](O)c1ccccc1
Reaction time: 24 h

Procedure:
Washed phaseolus aureus L (green grams) 500 g. were taken into a conical flask and allowed to soak in deionised water (4 L) for a period of 24 hr. Acetophenone (5 g; 0.0416 moles) I(a) was added to the soaked phaseolus aureus L (green grams) in the above water, covered and allowed to shake for 24 hr at room temperature (28° C). Then the green grams were filtered off and washed with deionised water (5×600 ml). The combined filtrate was extracted with chloroform (30×500 ml). The chloroform layer was dried and the crude product obtained (3.21 g.). Pure 1-phenyl-(1S)-ethan-1-ol II(a) was obtained after column chromatography with silica gel using chloroform as eluent.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[BH4-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CO)cnc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.55 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 200 ml. of ethanol, a solution of 1.9 g. of NaBH4 in 150 ml. of ethanol is added at about -4° C. After stirring for 15 minutes at 0° C., the excess of NaBH4 is decomposed with 10% hydrochloric acid and the reaction mixture is filtered. the residue, which is obtained by evaporation of the filtrate, is crystallized from acetone and yield 1 g. of the title product which melts at 142°-144° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH3:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[Cl:19].CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:20][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH3:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CSc1ccc(Cl)nc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1C#N

Procedure:
6-Chloro-3-methylthio-2-pyridinecarbonitrile was mixed with 16.3 g of 3,4-dichlorophenol in the presence of 11.2 g of t-BuOK in 150 ml THF and 15 ml of DMSO. 13.4 g (54%) of the desired, 6-(3,4-dichlorophenoxy)-3-methylthio-2-pyridinecarbonitrile was recovered, m.p. 156°-158° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:18]3[N:17]=2)=[CH:9][C:8]([F:28])=[CH:7][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:8]1[CH:9]=[C:10]2[C:5](=[N:6][CH:7]=1)[NH:4][CH2:3][CH2:2][NH:1][C:25](=[O:27])[C:24]1=[C:18]3[N:17]=[C:16]([CH:21]=[CH:20][N:19]3[N:22]=[CH:23]1)[N:12]1[C@@H:11]2[CH2:15][CH2:14][CH2:13]1
Reactant: NCCNc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NCCNc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a DMF (3 mL) solution of (R)-5-(2-(2-(2-aminoethylamino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.065 mmol) was first added HATU (29 mg, 0.077 mmol), followed by five-minute stirring and then drop-wise addition of DIEA (56 μL, 0.32 mmol). After stirring at ambient temperature overnight, the reaction was directly purified by reverse phase column chromatography (Biotage SP4 system C18 25+M cartridge, acetonitrile/water 5 to 45%), to yield the title product as off-white solid (7 mg, 30% yield). MS (apci) m/z=368.2 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:25][CH2:24][C:14]3([CH2:23][CH2:22][C:17]4(OCC[O:18]4)[CH2:16][CH2:15]3)[C:13]2=[O:26])=[CH:8][CH:7]=1.Cl>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:25][CH2:24][C:14]3([CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]3)[C:13]2=[O:26])=[CH:10][CH:11]=1
Reactant: COCCCc1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COCCCc1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
10-[4-(3-Methoxy-propyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (460 mg, obtained in example 130, step 3) was dissolved in tetrahydrofuran (12 mL). Then hydrochloric acid (2M, 6.40 mL) was added dropwise over a period of 10 minutes and the mixture was stirred for 3 hours at RT. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless solid (128 mg, 32%). MS (m/e): 316.2 [MH+].
Reaction SMILES: C1C2C(=C(CCNC)C=CC=2)CC1.[C:14]1([CH:20]2[CH2:22][O:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH:20]([OH:21])[CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C2CO2)cc1
Agent: CNCCc1cccc2c1CCC2
Product: CC(O)c1ccccc1

Procedure:
2- 2-(Indan-4-yl)ethyl!methylamino!-1-phenylethanol was synthesized in analogy to example 1D from 2-(indan-4-yl)ethyl-N-methylamine and phenyloxirane.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.F[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][C:36]([F:39])([F:38])[F:37]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:30]=[CH:31][CH:26]=[C:27]([O:35][C:36]([F:37])([F:38])[F:39])[CH:28]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1ccc(F)c(OC(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(OC(F)(F)F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 13.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-fluoro-3-(trifluoromethoxy)phenylboronic acid (20 mg, 0.106 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-(trifluoromethoxy)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (3.32 mg, 14%). 1H-NMR (MeOD): 2.23 (m, 2H), 3.10 (s, 3H), 5.80 (d, 1H), 6.98 (m, 1H), 7.13 (m, 1H), 7.26 (m, 2H), 7.34 (m, 3H), 7.38 (m, 3H), 7.46 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CS(C)=O>[C:10]1([S:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Yield: 378.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (6 g, 48 mmol), sodium benzenesulfinate (7.5 g, 4.6 mmol), and dimethylsulfoxide (30 mL) was heated at 100° C. for 20 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give a white solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was purified using flash chromatography (Analogix SuperFlash™ column, 15%-40% ethyl acetate in hexanes) to give 4.29 g (41%) of 4-(benzenesulfonyl)-benzaldehyde as a white solid.