Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(C=C)OB([CH:39]=[CH2:40])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.CCOC(C)=O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:39]=[CH2:40])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 90 °C
Yield: 209.8 %

Procedure:
4′-(4-Bromo-2-ethoxy-5-formylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (30.0 g, 59.6 mmol), 2,4,6-trivinylcyclo-triboroxane pyridine complex (5.74 g, 23.8 mmol), tetrakis(triphenylphosphine) palladium(0) (689 mg, 596 μmol), potassium carbonate (8.2 g, 59.6 mmol), 1,2-dimethoxyethane (266 mL, 2560 mmol), and water (107 mL, 5960 mmol) were combined. The solution was heated at 90° C. for 4 hours. After cooling to room temperature, EtOAc (300 mL) and water (100 mL) was added. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by silica gel chromatography (5-30% EtOAc:hexanes) to yield compound A (22.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]Br.C(Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Br:11][C:9]1[C:2]([CH3:1])=[C:3]([C:6]([CH3:10])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: BrBr
Reactant: Cc1cccc(C)c1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(Br)c(C)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-dimethylbenzonitrile (5.0 g, 38.0 mmol), bromine (1.9 ml, 38.0 mmol) and chloroform (10 ml) is stirred at room temperature for 24 hours and subsequently heated to 60° C. for 6 hours. Upon cooling down to 0° C., 10 g of AlCl3 are added and the mixture is stirred for 4 hours at 0° C. The reaction mixture is poured into water and extracted with toluene. The organic phase is separated and concentrated and the residue is purified by column chromatography yielding the pure product as brown crystals, 6.2 g, mp. 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]([OH:44])[CH2:41][NH:42][CH3:43])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:42]([CH2:41][CH:40]([OH:44])[C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH3:26])[CH:35]=4)[CH3:43])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1cccc(OCCOCCOC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCCOc1cccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (85 mg, 0.21 mmol), 1-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}-2-(methylamino)ethanol (Preparation 44) (85 mg, 0.32 mmol) and diisopropylethylamine (56 μL, 0.32 mmol) in dry DMF (4.4 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with ice (6 g). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (10 mL, 1:1, v/v, dissolved with warming acetonitrile, diluted with water and then cooled to 0° C. overnight) gave the title compound (107 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1[CH:20]=O>>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH3:14])[CH3:15])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Yield: 64 %

Procedure:
The title compound was prepared in an analogous manner as Ex-1 using 4-acetyl-N,N-dimethyl-benzenesulfonamide (Ex-31A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 64% yield, yellow solid, mp 120–122° C. 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=16 Hz, 1H), 8.12 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22–7.27 (m, 1H), 7.11–7.16 (m, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H), 2.74 (s, 6H). HRMS (ESI) Calcd. for C28H28N2O5S: 505.1797 (M+H)+; Found: 505.1797.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(F)ccc4F)c3O2)cc1
Product: CNCC1Cc2cccc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.027 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.060 g, 0.14 mmol) and methylamine (0.045 g, 1.4 mmol). mp 172-174° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]>C(#N)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2)c1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1

Procedure:
The title compound was prepared from methyl 2-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (EXAMPLE 98) according to the procedure for the preparation of Example 97, part B. 1H NMR (400 MHz, DMSO-d6): δ 5.41 (2H, s), 6.00 (1H, d, J=2.0 Hz), 7.61 (1H, d, J=1.6 Hz), 7.67-7.69 (2H, m), 7.77 (1H, dd, J=0.8 Hz, J=4.8 Hz), 7.87-7.89 (2H, m), 8.10 (1H, s), 8.70 (1H, d, J=5.2 Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.104 min. [M+H] Calc'd for C17H12N4O3, 321. Found, 321.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([O:22][CH2:23][C:24]([CH2:28][OH:29])([CH3:27])[CH2:25][OH:26])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:34](Br)[C:35]#[CH:36].C(Cl)Cl>C1COCC1.O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C:24]([CH2:28][O:29][CH2:36][C:35]#[CH:34])([CH3:27])[CH2:25][OH:26])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)=[CH:9][CH:10]=1
Reactant: C#CCBr
Reactant: COc1ccc(C(OCC(C)(CO)CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C#CCOCC(C)(CO)COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
1-O-(4,4′-dimethoxytrityl)-2-hydroxymethyl-2-methyl-1,3-propanediol 16 (620 mg, 1.47 mmol) was dissolved in anhydrous THF (6 mL) and sodium hydride (60% in oil, 590 mg, 14.7 mmol) was added. After 10 min stirring, propargyl bromide (80% in toluene, 650 mL, 5.9 mmol) was added and the mixture was stirred at RT for 1 h. Then CH2Cl2 was added (100 mL) and 2 mL of water. Organic layer was washed with water (2×100 mL) and dried over Na2SO4. After evaporation the residue was purified by flash chromatography using an increasing amount of ethyl acetate (10% to 50%) in cyclohexane containing 1% of triethylamine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[N:12]1([C:18]2[C:23](=[O:24])[NH:22][CH:21]=[C:20]3[CH2:25][N:26]([CH2:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[C:27](=[O:28])[C:19]=23)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(#N)C>[CH3:5][O:4][CH2:3][CH2:2][N:22]1[C:23](=[O:24])[C:18]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:19]2[C:27](=[O:28])[N:26]([CH2:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:25][C:20]2=[CH:21]1
Reactant: COCCBr
Reactant: O=C1c2c(c[nH]c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 120 °C
Reaction time: 12 h
Yield: 4.8 %

Procedure:
A solution of 1-bromo-2-methoxyethane (32.0 mg, 0.231 mmol), potassium carbonate (159 mg, 1.153 mmol) and 7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (90 mg, 0.231 mmol, see Example 15) were suspended in acetonitrile (50 ml) in a round-bottomed flask. The suspension was stirred at about 120° C. for about 12 h. The obtained crude material was purified by preparative HPLC to give the title compound (5 mg, 0.011 mmol, 4.84% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:3]=1.[F:12]F.O1CCCC1.C(OCC)C>C(#N)C.O>[F:12][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[S:8]([O-:11])(=[O:10])=[O:9]
Reactant: Cc1ccnc(S(=O)(=O)O)c1
Reactant: FF
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc[n+](F)c(S(=O)(=O)[O-])c1

Procedure:
In a reactor, 4-methylpyridine-2-sulfonic acid (3.46 g, 20 mmol) was dissolved in a mixture of acetonitrile (60 ml) and water (6 ml). The reactor was dipped in a cooling bath kept at -20° C., and fluorine gas diluted with nitrogen gas to a concentration of 10% was introduced at a flow rate of 40 ml/min. A total amount of the fluorine gas was 1334 ml (60 mmol). Then, the nitrogen gas alone was introduced at a flow rate of 36 ml/min. for 30 minutes. After the addition of tetrahydrofuran and ethyl ether at -20° C., a crystalline precipitate was recovered by filtration at room temperature. The crystal was washed with ethyl ether and dried under reduced pressure to obtain crystalline N-fluoro-4-methylpyridinium-2-sulfonate (3.04 g, 15.9 mmol). Yield, 80%. A melting point is shown in Table 1. IR and NMR data are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[C:6](=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:7]=O.[CH3:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][S:21]([CH2:24][C:25]([OH:27])=[O:26])(=[O:23])=[O:22])=[CH:18][CH:17]=1>C(O)(=O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][S:21]([C:24]2[C:25](=[O:27])[O:26][C:5]3[C:6]([CH:7]=2)=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:22])=[O:23])=[CH:28][CH:29]=1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Reactant: COc1cc(O)c(C=O)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3c(OC)cc(OC)cc3oc2=O)cc1
Yield: 58 %

Procedure:
A solution of 4,6-dimethoxysalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 58% yield of the title compound; m.p. 183-185° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([P:12]2(=[O:21])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N12CCCCC1C=NCCC2.O1CCCC1>C(OCC)C>[C:6]1([P:12]2(=[O:21])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]2[C:3](=[O:4])[CH2:2][Cl:1])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: O=P1(c2ccccc2)NCc2ccccc21
Agent: C1=NCCCN2CCCCC12
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCl)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
Chloroacetyl chloride (0.8 g, 0.0072 mol) was added to a suspension of 1-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.5 g, 0.00656 mol) and 1,5-diazabicyclo[5.4.0]undec-5-ene in 25 ml. of tetrahydrofuran with constant stirring. The reaction mixture was heated at reflux for 30 minutes, then stirred for 16 hours at 26° C. The reaction mixture was concentrated using a rotary evaporator and the residue was partitioned between chloroform and water. The chloroform layer was separated, and washed with 5% hydrochloric acid, a 5% sodium bicarbonate solution and then with water. The chloroform layer was dried over magnesium sulfate, concentrated in vacuo and the resulting residue was slurried in anhydrous ether to yield a crystalline solid. The crystalline solid was further purified using a silica gel column with ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in diethyl ether to yield 1-phenyl-2-chloroacetyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.9 g, 45% yield) as a solid having a melting point of 167°-169° C. and the following analysis:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.CN([CH:27]=[O:28])C>C1COCC1>[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:4]2[CH:5]=[C:6]3[C:11](=[C:2]([CH:27]=[O:28])[CH:3]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)=[CH:14][CH:15]=1
Reactant: Brc1cc(Cc2ccncc2)cc2cccnc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(Cc2ccncc2)cc2cccnc12
Temperature: 25 °C

Procedure:
To a solution of 8-bromo-6-(pyridine-4-ylmethyl)quinoline (1 eq.) in THF (0.13 M) was added, at −78° C., n-butyl lithium (2.5 M hexane solution, 1.1 eq) dropwise over 15 min. The reaction mixture was stirred at −78° C. for a further 30 min before DMF (1.5 eq.) was slowly added. The resulting solution was allowed to warm to RT over 3 h and then quenched with H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>COCCOC>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1Br
Reactant: C1COCCN1
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(Br)cc1N1CCOCC1
Temperature: 90 °C

Procedure:
A mixture of 2,4-dibromo-1-(methylsulfonyl)benzene (0.3 g, 0.96 mmol) and morpholine (0.25 g, 2.9 mmol) in DME was heated at 90° C. for 16 h, cooled, and concentrated in vacuo. The crude residue was dissolved in EtOAc and washed with brine (2×). The organic layer was dried (MgSO4), concentrated to give a near colorless solid which was ˜1:1 mixture of regioisomers by analytical HPLC and LC/MS analysis. This residue was purified by chromatography on silica gel (EtOAc/hexanes) to afford 4-(5-bromo-2-(methylsulfonyl)phenyl)morpholine as a near colorless solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.2 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 3.8-3.6 (m, 4H), 3.4 (s, 3H), 3.1-2.9 (m, 4H). MS (ESI) 322.1, 320.1 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][CH2:21]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate (400 mg, 0.96 mmol, 1.00 equiv) and triethylamine (0.27 mL, 2.00 equiv) in dichloromethane (20 mL) was added dropwise MsCl (164 mg, 1.43 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2×40 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 379 mg (80%) of tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:20]([O-])=O)[CH:8]=2)[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:20])[CH:8]=2)[CH2:3]1
Reactant: CC1(C)Cc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)C1O
Agent: [Pd]
Solvent: CO
Product: CC1(C)Cc2ccc(N)cc2C(n2ccccc2=O)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-nitro-1,2,3,4-tetrahydro-3-naphthol in 24 ml of methanol is hydrogenated at 20° and 1 bar over 0.5 g of 5% Pd-on-C until hydrogenation ceases. The mixture is filtered and evaporated and worked up in the customary manner (using dilute sodium hydroxide/methylene dichloride) to give 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-amino-1,2,3,4-tetrahydro-3-naphthol.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]1=[O:14])[CH3:2].[N+:15]([CH2:17][C:18]1[N:22]=[C:21]([CH:23]2[CH2:25][CH2:24]2)[O:20][N:19]=1)#[C-:16]>>[CH:23]1([C:21]2[O:20][N:19]=[C:18]([C:17]3[N:15]=[CH:16][N:6]4[C:7]5[CH:12]=[CH:11][CH:10]=[N:9][C:8]=5[N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]=34)[N:22]=2)[CH2:25][CH2:24]1
Reactant: CCn1c(=O)c(=O)[nH]c2cccnc21
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Product: CCn1c(=O)c2c(-c3noc(C4CC4)n3)ncn2c2cccnc21

Procedure:
3-(5-cyclopropYl-1,2,4-oxadiazol-3-yl)-5-ethyl-4,5-dihydro4-oxo-imidazo(1,5-a)pyrido(2,3-e)pyrazine was prepared from 4-ethyl-1,2,3,4-tetrahydro-2,3-dioxo-pyrido(2,3-e)pyrazine and 3-isocyanomethyl-5-cyclopropyl-1,2,4-oxadiazole. M.p. 254.3°-255.4° C.
Reaction SMILES: [CH3:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3].O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[F:24][C:25]([F:41])([F:40])[C:26](=[O:39])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[CH3:38])([CH3:30])[CH3:29]>C1COCC1.C1CCCCC1>[F:41][C:25]([F:24])([F:40])[C@@:26]([CH2:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3])([OH:39])[CH2:27][C:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[CH3:38])([CH3:30])[CH3:29]
Reactant: Cc1ccc([S@@](C)=O)cc1
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
To a suspension of (R)-(+)-methyl p-tolylsulfoxide (23.6 g, 153 mmol) in 200 mL of anhydrous THF at −78° C. was added lithium diisopropylamide mono(tetrahydrofuran) (LDA), 1.5 M solution in cyclohexane, 102 mL, 153 mmol) over 20 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (36.4 g, 139 mmol) was then added via cannula with the aid of 125 mL of THF over 30 minutes. After 1.5 hours at −78° C., the reaction mixture was quenched with 600 mL of water and extracted with two 500 mL portions of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 10%-30% EtOAc/hexanes) afforded sequentially (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (31.9 g, 55%, 99% de) and (R)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol.
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16]([O-:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH:26]1([NH2+]C2CCCCC2)CCCCC1.C[Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:26][O:17][C:16](=[O:18])[C@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)[O-])c1ccc(Cl)cc1
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
A 0.5 N potassium bisulfate aqueous solution (7.9 mL) was added to a suspension of dicyclohexylammonium (R)-t-butoxycarbonylamino-(4-chloro-phenyl)acetate (605.6 mg, 1.30 mmol) in ether (16 mL), and the mixture was stirred for 10 minutes. Then, the aqueous layer was extracted with ether. The organic layer was washed with water and then brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in benzene (3.6 mL) and methanol (1.8 mL). A solution of trimethylsilyldiazomethane in ether (2 M, 0.71 mL, 1.43 mmol) was added dropwise under cooling with ice, and then the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (378.9 mg, 97%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.