Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[CH:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[N+:21]([O-])=O)[CH3:5].[H][H]>O1CCCC1.[Ni]>[CH3:1][O:2][CH:3]([O:24][CH3:25])[CH:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH2:21])[CH3:5]
Reactant: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1N

Procedure:
A solution of 2-[5-(benzyloxy)-2-nitroanilino]propionaldehyde dimethyl acetal (24.0 g, 0.0715 mole) in tetrahydrofuran is treated with Raney nickel (10 g) and placed in a Parr shaker hydrogenation apparatus under 20.5-37 psig hydrogen at ambient temperature. After the uptake of the theoretical quantity of hydrogen, the mixture is filtered and the filtrate is concentrated in vacuo to afford the title product as a dark-colored syrup. The product is identified by infrared and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6].CCN(CC)CC.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH:4]([CH2:5][CH3:6])[CH2:3][O:2][CH3:1])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)COC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(COC)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of 1-methoxy-2-butanol (52.08 g, 57.23 mL, 0.5 mol) and Et3N (108.2 mL, 0.75 mol, 1.5 equiv) in CH2Cl2 (500 mL) was treated dropwise with methanesulfonyl chloride (68.73 g, 46.44 mL, 0.6 mol, 1.2 equiv) at 0° C. under N2. The reaction mixture was warmed to 25° C. and stirred at 25° C. for an additional 4 h before being quenched with H2O (300 mL). The two layers were separated, and the aqueuos was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were washed with H2O (2×200 mL) and saturated aqueuos NaCl (200 mL), dried (MgSO4), and concentrated in vacuo. The residue was dried enough in vacuo to afforded the desired mesylate 1 (85-90.0 g, 91 g theoretical, 93-98%) as a pale-yellow oil, which was pure enough and directly used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]([C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:3](O)=[O:4].[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH:26]1([CH2:29][NH:30][C:3](=[O:4])[CH:2]([CH3:1])[C:6]([NH:8][CH:9]2[C:15](=[O:16])[N:14]([CH3:17])[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]2=3)=[O:7])[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C(=O)NCC1CC1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid (20 mg, 0.059 mmol) and cyclopropylmethylamine (5 mg, 0.059 mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2 ml). TPTU (2-(2-pyridon-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 19 mg, 0.065 mmol) was added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=392.2 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCc1ccc(Cl)c(Cl)c1
Yield: 84.3 %

Procedure:
To a solution of 3,4-dichlorobenzylamine (3.97 g) and triethylamine (3.5 ml) in chloroform (80 ml) was added a solution of 2-nitrobenzenesulfonyl chloride (5 g) in chloroform (20 ml) at 0° C. with stirring and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed successively with diluted hydrochloric acid and water, and then dried. Evaporation of the solvent gave N-(3,4-dichlorobenzyl)-2-nitrobenzenesulfonamide (6.87 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23]Br>>[Cl:18][C:7]1[CH:6]=[CH:5][C:4]2[N:3]3[CH2:20][CH2:21][CH2:22][CH2:23][N:1]=[C:2]3[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:11])[C:9]=2[CH:8]=1
Reactant: NC1=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: BrCCCCBr
Product: OC1(c2ccccc2)C2=NCCCCN2c2ccc(Cl)cc21
Yield: 30.1 %

Procedure:
2-Amino-5-chloro-3-phenyl-3H-indol-3-ol (5.16 g) was heated under reflux with 1,4-dibromobutane (4.32 g) for 24 hours. After cooling the solid was filtered off affording 1.88 g of the title compound as its hydrobromide, m.p. 298°-300°C (decomp.) after recrystallization from methanol/ethyl acetate.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]([CH:14]=[CH:15][C:16]([CH3:20])(O)[CH:17]=[CH2:18])=[C:8]([CH3:21])[C:7]1=[O:22])=[O:4].C(O)=[O:24].O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]([CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][CH2:18][OH:24])=[C:8]([CH3:21])[C:7]1=[O:22])=[O:4]
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C
Reactant: O=CO
Solvent: ClCCl
Solvent: O
Product: CC(C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C)=CCO
Reaction time: 0.75 h

Procedure:
47.8 g of 5-[4(S)-(chloroacetoxy)-3-oxo-2,6,6-trimethyl-cyclohex-1-en-1-yl]-3-methyl-penta-1,4-dien-3-ol are dissolved in 720 ml of methylene chloride. After the addition of 200 ml of formic acid, the solution is stirred at room temperture for 45 minutes, then introduced into water and extracted with diethyl ether. The ether extract is evaporated. The residue is taken up in 500 ml of methanol, treated with 100 g of potassium carbonate 250 ml of water, stirred for 1 hour, then introduced into water and extracted with ethyl acetate. The 5-[4(S)-(chloroacetoxy)-3-oxo-2,6,6-trimethyl-cyclohex-1-en-yl]-3-methyl-penta-2,4-dien-1-ol isolated from the extract is processed further as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:22].CS([C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1)=O.C(N(CC)C(C)C)(C)C>COCCO.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:22][C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1
Reactant: COc1cc(N2CCN(C3CCN(C)CC3)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 180 °C
Yield: 53.6 %

Procedure:
A solution of 2-methoxy-4-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-phenylamine (140 mg, 0.45 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (65 mg, 0.23 mmol) in 2-methoxyethanol (0.50 mL) was treated with N,N-diisopropylethylamine (59 uL, 0.34 mmol). The reaction was heated under microwave conditions at 300 watts at 180° C. for 90 minutes. The mixture was diluted with methanol (10 mL), filtered and concentrated. The residue was purified by preparative RP-HPLC to give 65 mg of an amber amorphous powder. MS=528 (M-TFA+H); NMR (DMSO-d6, ppm): 10.15 (s, 1H), 9.83 (s, 1H), 8.92 (s, 1H), 7.92 (d, J=9 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.43 (t, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 6.95 (q, J=5 Hz, 14 Hz, 1H), 6.73 (s, 1H), 6.45 (d, J=9 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.61 (m, 4H), 3.48 (m, 2H), 3.22 (m, 2H), 3.00 (m, 4H), 2.80 (s, 3H), 2.67 (m, 1H), 2.37 (m, 2H), 1.88 (m, 2H).
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[C:9](#[N:12])[CH2:10][OH:11].Cl.[OH2:14]>>[C:9](#[N:12])[CH2:10][OH:11].[C:10]([OH:11])(=[O:2])[CH2:9][OH:14].[C:9]([NH2:12])(=[O:14])[CH2:10][OH:11]
Reactant: O
Reactant: O=P([O-])([O-])[O-]
Agent: Cl
Agent: N#CCO
Agent: [K+]
Product: NC(=O)CO
Product: O=C(O)CO

Procedure:
The reaction described in Example 1 is repeated except that the mutant strains A. facilis 72-PF-15 or 72-PF-17 are used instead of A. facilis 72W. A suspension of 0.50 g (wet cell paste) A. facilis 72-PF-15 or 72-PF-17 in 8.44 mL of 0 020 M potassium phosphate buffer (pH 6.0) is placed into a 15-mL polypropylene centrifuge tube. To the tube is then added 1.06 mL of a 55 wt % solution of glycolonitrile in water (1.0 M final concentration of glycolonitrile in the suspension), and the resulting suspension mixed on a rotating platform at 25° C. Samples of the suspension for analysis (0.200 mL) are first adjusted to pH 2.5 with 6 N HCl to stop the reaction, centrifuged, and the supernatant filtered using a 0.2 micron filter. After sufficient time, complete conversion of glycolonitrile to glycolic acid is obtained with no production of byproduct glycolamide.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]([C:31]3[CH:39]=[C:38]([O:40][CH3:41])[C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH3:30])(=[O:21])=[O:20])=[O:17])=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4].O.Cl>C(O)C.O1CCOCC1>[OH:4][CH2:3][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]([C:31]3[CH:39]=[C:38]([O:40][CH3:41])[C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[O:29][CH3:30])(=[O:21])=[O:20])=[O:17])=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
Sodium borohydride (9 mg) was added to a suspension of 6-formyl-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 96, 130 mg, 0.24 mmol) in a mixture of ethanol (3 ml) and 1,4-dioxane (3 ml) at ambient temperature. Stirring was continued for 1.5 hours, and then water was added dropwise until a solution was achieved. After carefully acidifying with drops of concentrated hydrochloric acid, the solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic layer was separated and rewashed with water. The organic layer was dried (magnesium sulphate) and the solvents removed in vacuo. The residue was crystallised from a mixture of methanol and diethyl ether to give the title compound (105 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](F)=[C:5]([N+:10]([O-])=O)[CH:4]=1)#[N:2].[CH3:13][O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][O:20][CH3:21].[H][H]>C(#N)C.[Ni]>[NH2:10][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N:17]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:15][O:14][CH3:13])[C:1]#[N:2]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Reactant: COCCNCCOC
Agent: [Ni]
Solvent: CC#N
Product: COCCN(CCOC)c1ccc(C#N)cc1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-1-fluoro-2-nitrobenzene (35.1 mg, 0.2 mmol) and N,N-bis(2-methoxyethyl)amine (0.266 g, 2.4 mmol) in acetonitrile (10 mL) in a capped 20-mL vial was shaken at 80° C. overnight and concentrated. The concentrate was dissolved in methanol (10 mL), treated with Raney nickel (50% water suspension, 0.40 g, 6.8 mmol), filled with excess hydrogen, shaken at 50° C. for 1 hour, and filtered. The filtrate was concentrated and the concentrate was purified by HPLC with acetonitrile/water containing 0.1% TFA to give the desired compound. MS (APCI(+)) m/z 250 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS([Cl:39])(=O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([Cl:39])[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-1-diphenylmethyl-3-azetidinol (15) (4.0 g) and N,N-diisopropylethylamine (3.2 mL) in dichloromethane (100 mL) at 0° C. was added, dropwise, methanesulfonyl chloride (125 mL). The mixture was stirred at 0° C. for 18 hrs, then washed (water, brine) and dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from hexane to give 3-(4-fluorophenyl)-3-chloro-1-(diphenylmethyl)azetidine (16) (22 g), m.p. 108-109° C. (hexane). Found: C, 75.13; H, 5.46; N, 3.93. C22H19CIFN C, 75.10; H, 5.44; N, 3.98%.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[H][H]>CO.O>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH:4]([OH:5])[C:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(=O)c2ccc(Cl)cc2Cl)CCCC1
Solvent: O
Solvent: CO
Product: CCOC(=O)C1(C(O)c2ccc(Cl)cc2Cl)CCCC1
Yield: 51.2 %

Procedure:
(S)-tBuBisP*-RuBr2 (16 mg) was placed in a reactor and deaerated. After substitution with argon, a mixture of ethyl 1-(2,4-dichlorobenzoyl)cyclopentanecarboxylate (2.8 g, 5.6 mmol) and methanol-water (101) (30 ml) was added. Under 70° C. and hydrogen pressure (6 kg/cm2), the mixture was stirred for 30 h and concentrated. This was diluted with ethyl acetate (50 ml), washed with water and concentrated to dryness. This was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (0.91 g, 41.3%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 92%.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]2[N:29]([CH3:30])[N:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:23][CH:24]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:36][I:37]>C(Cl)Cl>[I-:37].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[S:21][C:22]([C:25]2[N:29]([CH3:30])[N:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:19])[CH2:3][N+:2]([CH3:36])([CH3:1])[CH3:35])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Reactant: CI
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)C[N+](C)(C)C)s1
Product: [I-]
Reaction time: 8 h

Procedure:
To a solution of (R)-benzyl 4-(dimethylamino)-3-(5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonamido)butanoate in CH2Cl2 (2 mL) was added methyl iodide (100 μL). The reaction was stirred overnight and concentrated to dryness to give the title compound in quantitative yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O.CN(C=O)C.[OH:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[CH3:36])[NH2:32]>C(O)(C)C>[ClH:21].[OH:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[CH3:36])[NH:32][C:12]1[C:11]2[C:16](=[CH:17][C:8]([S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:9][CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(N)cc1O
Reactant: O=c1[nH]cnc2cc(Sc3ccncc3)ccc12
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ncnc3cc(Sc4ccncc4)ccc23)cc1O
Product: Cl
Yield: 73 %

Procedure:
A mixture of 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (100 mg, 0.4 mmol), thionyl chloride (20 ml) and DMF (0.1 ml) was heated at reflux for 1.5 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene. A solution of 3-hydroxy-4-methylaniline (53 mg, 0.04 mmol) in isopropanol (10 ml) was added to the solid residue and the mixture was heated at reflux for 2 hours. The mixture was allowed to cool and the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(3-hydroxy-4-methylanilino)-7-(4-pyridylthio)quinazoline hydrochloride(103 mg, 73%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:18][CH:17]([OH:19])[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[CH3:39][S:36]([O:19][CH:17]1[CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:5]3[N:4]=[C:3]([C:20]4[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:2]([F:1])=[CH:7][N:6]=3)=[CH:10][CH:11]=2)[CH2:18]1)(=[O:38])=[O:37]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(O)C4)cc3)ncc2F)n1C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(OS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Temperature: 0 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
To an ice cooled solution of 1-(4-{[5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}phenyl)azetidin-3-ol (Example 137; 0.728 g, 1.905 mM) and triethylamine (153 μl, 2.09 mM) in dry DCM (22 ml), mesyl chloride (162 μl, 2.09 mM) was added. The reaction was stirred at 0° C. for 30 minutes and at room temperature for 20 hours. The reaction mixture was diluted with more DCM and extracted in turn with water (twice), saturated sodium chloride, dried with anhydrous sodium sulphate, filtered and evaporated to give the title compound as a brown foam (717 mg, 82%). NMR 1.37 (d, 6H), 2.48 (s, 3H+DMSO), 3.25 (s, 3H), 3.82 (m, 2H), 4.2 (m, 2H), 5.4 (m, 2H), 6.45 (d, 2H), 7.35 (m, 3H), 8.42 (d, 1H), 9.13 (s, 1H); m/z 461.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>C(#N)C>[Br:19][C:12]1[C:13]([NH:15][CH2:16][C:17]#[CH:18])=[N:14][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:31]3[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=3)(=[O:35])=[O:34])=[CH:3][CH:4]=2)=[N:10][CH:11]=1
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCNc1nc(Nc2ccc(NS(=O)(=O)c3cn(C)cn3)cc2)ncc1Br

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (100 mg, 0.3 mmole prepared in analogy to procedure 21) was dissolved in acetonitrile (10 ml) and triethylamine (1 ml) and 1-Methyl-1H-imidazole-4-sulfonyl chloride (120 mg, 0.66 mmole) was added at room temperature. The reaction mixture was stirred under reflux for 5 hours, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (ethyl acetate: hexanes 1:1). Yield 41 mg of 1-Methyl-1H-imidazole-4-sulfonic acid [4-(5-b bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-amide. ESI-MS: 463.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 40 °C
Reaction time: 6 h

Procedure:
140 mg of (RS)-methyl 4-[2-(4,4-dimethyl-thiochroman-6-yl)-heptyloxy]-benzoate, dissolved in 20 ml THF/5 ml H2O/5 ml methanol, was treated with 200 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 5 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 20 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 10 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (10% methanol/methylene chloride), yielding a colorless oil. Trituration in hexanes provided a white solid, m.p. 168-169° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:12]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: OB(O)C1=CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(C2=CCCCC2)n1
Yield: 61 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and cyclohexenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-cyclohexenyl-5-fluoropicolinic acid in 61% yield. LC/MS=222.0 (M+H), Rt=0.52 min.