Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)COC1C=C(C)C(SC2C=CC(C[NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=CC=2C)=CC=1C)C.[CH2:36]([O:38][C:39](=[O:62])[CH2:40][O:41][C:42]1[C:51]2[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=2[C:45]([S:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]=O)=[CH:55][C:54]=2[Cl:61])=[CH:44][CH:43]=1)[CH3:37]>>[CH2:36]([O:38][C:39](=[O:62])[CH2:40][O:41][C:42]1[C:51]2[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=2[C:45]([S:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)=[CH:55][C:54]=2[Cl:61])=[CH:44][CH:43]=1)[CH3:37]
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)cc1C
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)c2c1CCCC2
Product: CCOC(=O)COc1ccc(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 21.5, using compound 22.4 as the starting material. 1H NMR (300 MHz) (CDCl3) δ 7.38 (2H, d, J=8.6 Hz); 7.34 (1H, d, J=8.6 Hz); 7.33 (1H, s); 6.99 (1H, dd, J=1.5, 7.9 Hz); 6.58 (3H, d, J=7.1 Hz); 6.49 (1H, d, J=8.2 Hz); 4.67 (2H, s); 4.37 (1H, brt); 4.28 (2H, q, J=7.2 Hz); 4.28 (2H, d, J=4.5 Hz); 2.78-2.74 (4H, m); 1.74-1.72 (4H, m); 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[Cl:9][C:3]1[C:2]2[N:1]=[C:19]([NH:18][C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:20][C:7]=2[N:6]=[CH:5][N:4]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1nc2c(Cl)ncnc2s1)c1ccccc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A mixture of 5-amino-4,6-dichloro-pyrimidine (5.0 g, 30.49 mmol) in acetone (30 mL) at 25° C. was treated with benzoyl isothiocyanate (5.5 g, 33.54 mmol). The mixture was stirred at reflux for 6 h and then was cooled to 25° C. The resulting solids were collected by filtration, washed with acetone and petroleum ether and dried in vacuo to afford N-(7-chloro-thiazolo[5,4-d]pyrimidin-2-yl)-benzamide (7.87 g, 79%) as an off-white solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].C1C=C(Cl)C=C(C(OO)=[O:21])C=1.FC1C(C2CO2)=CC(OC)=C(C=1)C#N>>[F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:11][O:21]2)[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(F)c(C#N)c(F)c1
Agent: COc1cc(C2CO2)c(F)cc1C#N
Product: N#Cc1c(F)cc(C2CO2)cc1F

Procedure:
2,6-Difluoro-4-(oxiran-2-yl)benzonitrile was prepared from 2,6-Difluoro-4-vinylbenzonitrile using m-CPBA in an analagous fashion to that described for 5-fluoro-2-methoxy-4-(oxiran-2-yl)benzonitrile (Step H) above: 1H NMR (500 MHz, CDCl3) δ 7.02 (d, J=8.0 Hz, 2H), 3.92 (dd, J=3.6, 2.4 Hz, 1H), 3.24 (dd, J=5.4, 4.0 Hz, 1H), 2.74 (dd, J=5.4, 2.4 Hz, 1H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=[O:11])[NH:3][CH:2]=1.OS(O)(=O)=O.[CH3:18]O>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:18])=[O:11])[NH:3][CH:2]=1
Reactant: O=C(O)c1ccnc2[nH]cnc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc2[nH]cnc12
Reaction time: 10 h
Yield: 80 %

Procedure:
Absolute methanol (30 ml) is added to acid x177 (2.0 g). Concentrated H2SO4 (4 ml) is added to the obtained suspension at 0° C. The reaction mixture is refluxed under protection from the air moisture and vigorous stirring for 10 h. After 3 h the solid is completely dissolved. The next morning the reaction mixture is evaporated to half-volume in the vacuum of a rotary evaporator and neutralized under cooling with ice with aqueous ammonia to pH 8-9. The formed precipitate is quickly separated by filtration, washed with ice-cold water (2×30 ml), and dried over P2O5 overnight to afford 1.74 g of methyl 3H-imidazo[4,5-b]pyridine-7-carboxylate x179.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=[N:23][OH:24])=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)C[CH2:31][C:30]1=O.C[Si](C#C)(C)C.[OH-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[CH:31]=[CH:30][O:24][N:23]=3)=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCc1c(C=NO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1c(-c2ccon2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.55 g (1.5 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime is dissolved in 30 ml of dry DMF and combined with 0.3 g (1.7 mmol) of N-bromosuccinimide (dissolved in 5 ml of DMF). The reaction mixture is stirred for 10 minutes at room temperature and then 1.5 eq. of trimethylsilylacetylene and 1 ml of triethylamine are added. After 4 hours of agitation at room temperature, 5 ml of 1-molar sodium hydroxide solution is added and subsequently agitation is continued for another hour. The solution is poured into ice water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent drawn off. The resultant product is purified by column chromatography on silica gel with ethyl acetate as the eluent. Melting point: 123°-126° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:26]1([CH:25]=[C:24]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=2)[C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COCCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 100 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine (343 mg, 0.59 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine (260 mg, quant.) as a white solid: LC/MS m/e calcd for C24H28N2O4S [M+H]+ 441.57, observed 441.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[OH-].[Na+:12]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S-:10])=[CH:5][CH:4]=1.[Na+:12]
Reactant: COc1ccc(CS)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C[S-])cc1

Procedure:
(4-methoxyphenyl)methanethiol is stirred in ethanol with sodium hydroxide to form sodium (4-methoxyphenyl)methanethiolate. An equivalent of 1-(chloromethyl)-4-methoxybenzene is added to the mixture, which is stirred overnight. The reaction mixture is then quenched by addition of dilute acid and the product bis(4-methoxybenzyl)sulfide. Subsequently, the bis(4-methoxybenzyl)sulfide is reacted with HBr in acetonitrile to cleave the methoxy protecting groups, followed by neutralization and purification of the bis(4-hydroxybenzyl)sulfide product.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[N:11][CH:12]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 4-{5-[(trimethylsilyl)ethynyl]pyridin-2-yl}piperazine-1-carboxylate (637 mg, 1.77 mmol), in THF (8 mL) at 25° C. was added tetrabutylammonium fluoride (1.77 mL, 1.0M in THF). The reaction was stirred for 1 hour. Water (5 mL) was then added and product extracted with ethyl acetate (2×5 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo to give tert-butyl 4-(5-ethynylpyridin-2-yl)piperazine-1-carboxylate as an orange solid (509 mg, 1.77 mmol, 100%).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.[NH2:29][C:30]1[N:38]=[C:37]2[C:33]([N:34]=[CH:35][NH:36]2)=[C:32](Cl)[N:31]=1>C(O)CCC>[NH2:29][C:30]1[N:38]=[C:37]2[C:33]([N:34]=[CH:35][NH:36]2)=[C:32]([N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[Cl:15])[N:31]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: Clc1ccccc1OC[C@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: Nc1nc(N2CCC[C@@H]2COc2ccccc2Cl)c2nc[nH]c2n1
Reaction time: 2.5 h
Yield: 57.2 %

Procedure:
7.1 93.84 μl of triethylamine are added dropwise to a mixture of 75 mg of (R)-2-(2-chlorophenoxymethyl)pyrrolidine trifluoroacetate and 39.5 mg of 2-amino-6-chloro-9H-purine in 1 ml of n-butanol. The reaction mixture is stirred at 100° for 2.5 hours. The mixture is cooled, the deposited precipitate is separated off, and the filtrate is chromatographed directly on a 12 g RP18 column. The isolated product fractions are subjected to conventional purification, giving 45.4 mg of 2-amino-6-[(R)-2-(2-chlorophenoxymethyl)-pyrrolidin-1-yl]-9H-purine (“A36”); HPLC retention time 2.77 minutes; gradient P2; [M+H]+ 345.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Br)c[n+]1[O-]
Product: COC(=O)c1ccc(Br)c(Cl)n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 5-bromo-2-(methoxycarbonyl)pyridine 1-oxide (22.0 g) was added phosphoryl chloride (40.0 mL), and the mixture was stirred at 90° C. for 10 min. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (16.0 g) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[C:10]([CH3:16])[CH:11]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.6 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-5-carboxylic acid (1.4 g), 5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.9 g) and diethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.3 g), melting point: 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][O:16][CH:11]3[O:10][N:9]=2)[CH:7]=1>Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]2[C:12]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:11][O:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1=NOC2OCCCC12
Agent: Cl
Solvent: O
Product: COc1ccc(Cl)cc1-c1nocc1CCCO
Yield: 67.9 %

Procedure:
Heat a solution of 3-(5-chloro-2-methoxyphenyl)-3a,5,6,7a-tetrahydro-4H-pyrano[3,2-d]isoxazole (12.0 g, 44 mmol) in 12 N HCl (200 mL) at 50° C. for 24 hours and then dilute the mixture with water (300 mL) and extract with ethyl acetate (3×200 mL). Wash the combined organic extracts with brine (100 mL), dry over Na2SO4 and remove the solvents under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1), to provide 3-[3-(5-chloro-2-methoxyphenyl)isoxazol-4-yl]propan-1-ol (8.0 g, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])=[CH:4][CH:3]=1.Cl[Sn]Cl>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)cc1
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A mixture of 3.10 g (8.40 mmol) 4-[(4-bromophenyl)amino]-6-nitro-quinoline-3-carbonitrile, 155 ml ethanol, and 9.47 g (42.0 mmol) SnCl2 dehydrate was heated to reflux under N2. After 4 hours, removed heat and added ice water. Made basic with sodium bicarbonate and stirred for 2 hours. With mixture still basic, extracted with chloroform, stirred organic layer with Darco and dried with sodium sulfate. Filtered, stripped solvent and dried in vacuo, giving 2.265 g of brown-yellow solid: mass spectrum (electrospray m/e): M+H=339.0, 341.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.[CH:38]([C:41]1[S:42][C:43]([C:46]([N:48]2[CH2:53][C:52]3([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[O:51][CH2:50][CH2:49]2)=[O:47])=[CH:44][N:45]=1)([CH3:40])[CH3:39].C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:56]2[CH2:55][CH2:54][C:52]3([O:51][CH2:50][CH2:49][N:48]([C:46]([C:43]4[S:42][C:41]([CH:38]([CH3:40])[CH3:39])=[N:45][CH:44]=4)=[O:47])[CH2:53]3)[CH2:58][CH2:57]2)=[CH:14][CH:13]=1)[C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.575 g) in MeCN (3 mL) was added dropwise to a solution of (2-isopropylthiazol-5-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 114, step b) (0.229 g) and triethylamine (0.21 mL) in MeCN (7.3 mL) at RT under argon. The resulting mixture was stirred at 80° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM (25 mL), washed with brine (20 mL) and water (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-8% MeOH in DCM to give the subtitled compound as a yellow solid. Yield 0.395 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH3:22])[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:9][CH:10]=C)([CH3:4])([CH3:3])[CH3:2].[O:24]=[O+][O-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH3:22])[N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:9][CH:10]=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN(C(=O)OCc1ccccc1)[C@H](C)C(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: C[C@H](C(=O)OC(C)(C)C)N(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Cbz-N-allyl-D-alanine t-butylester (70) in methylene chloride is treated with ozone at -78° C. until a blue color persists. The ozonide is quenched with dimethylsulfide and allowed to warm to room temperature. Excess dimethylsulfide is removed by bubbling a stream of nitrogen into the solution. After evaporation of solvent the product is purified by flash chromatography over silica gel to give (71).
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.O>CN(C)C=O>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2cnc3ccccc32)cc1
Temperature: 130 °C

Procedure:
Sodium hydride (60% strength in mineral oil; 24.0 g, 0.60 mol) is placed in a flask and admixed with N,N-dimethylformamide (80 ml). A solution of benzimidazole (73.3 g, 0.60 mol) in N,N-dimethylformamide (250 ml) is added dropwise to the suspension over a period of 1 hour. After H2 evolution has ceased 4-chlorobenzonitrile (55.6 g, 0.40 mol) is added and the mixture is subsequently heated at 130° C. for 10.5 hours. After cooling to room temperature, the reaction mixture is poured into water (4 I) and the residue formed is filtered off with suction, washed with water and dried under reduced pressure. This gives 90.6 g of 1-(4-cyanophenyl)benzimidazole which still comprises mineral oil as contaminant.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>CS(C)=O>[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:27][CH2:26]1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Br)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Br)c(Cl)cn2)CC1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To a solution of 3-bromo-5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (100 mg, 0.250 mmol) in DMSO (1 mL) was added trans-1,4-diaminocyclohexane (114 mg, 0.998 mmol). The mixture was stirred at 110° C. for 19 hr. The crude reaction mixture was purified by reverse phase HPLC and lyophilized to give 51 mg of N2′-(trans-4-aminocyclohexyl)-3-bromo-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 494.2/496.1 (MH+), retention time=0.61 min; 1H NMR (400 MHz, DMSO-d6) d ppm 1.06-1.31 (m, 4H) 1.31-1.49 (m, 2H) 1.49-1.64 (m, 2H) 1.64-1.82 (m, 1H) 1.85-2.11 (m, 4H) 2.93-3.12 (m, 3H) 3.22 (t, J=10.96 Hz, 2H) 3.61 (t, J=10.76 Hz, 1H) 3.81 (dd, J=11.35, 2.74 Hz, 2H) 6.39 (s, 1H) 6.48 (d, 1H) 6.82 (br. s., 1H) 6.94 (br. s., 1H) 7.59 (d, J=9.00 Hz, 1H) 7.78 (d, J=3.91 Hz, 2H) 8.02 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH:15]([CH3:17])[C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][C:12]=3[CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH:15]([CH3:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2OC1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)C(C)O3)cc1
Reaction time: 16 h
Yield: 78.8 %

Procedure:
To a solution of ethyl 6—(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxylate (3.0 g) in ethanol-tetrahydrofuran (30-30 ml) was added 1N sodium hydroxide (12 ml) at room temperature, and the mixture was stirred for 16 hours. Under reduced pressure, the solvent was evaporated and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 6—(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxylic acid (2.15 g) as yellow crystals.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][CH2:15][C:16]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[C:20]([B:31]2[O:35][C:34](C)(C)C(C)(C)[O:32]2)[C:17]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:34]1[O:35][B:31]([OH:32])[C:20]2[CH:21]=[C:22]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH:23]=[C:16]([CH2:15][O:14][CH3:13])[C:17]1=2)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: COCc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(COC)c21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A suspension of zinc (8.04 g, 123 mmol) in THF (80 mL) was added TMSCl (2.31 ml, 18.2 mmol) at 40° C. The temperature was increased to 55° C. over 30 min. Then, the temperature was lowered to 37° C. and ethyl 2-bromoacetate (12.6 mL, 114 mmol) was added slowly. The resulting solution was stirred for 30 min and cooled from 45° C. to room temperature and stood by for 1 h. The top clear layer (25 mL) was added to a solution of 2-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.56 g, 9.46 mmol) in THF (50 ml) at −78° C. After the addition, the reaction was warmed to 0° C. using an ice bath and stirred at 0° C. 30 min. The reaction mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=2:1) to afford the title compound (2.30 g, 67%). 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 1H), 7.11 (s, 1H), 5.73-5.70 (m, 1H), 5.46-5.44 (m, 1H), 4.54-4.39 (m, 2H), 4.21-4.16 (q, 2H), 3.94-3.90 (m, 1H), 3.66-3.60 (m, 1H), 3.38 (s, 3H), 3.18-3.11 (m, 1H), 2.43-2.34 (m, 1H), 1.88-1.85 (m, 2H), 1.70-1.61 (m, 4H), 1.26 (t, 3H).