Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:26]2
Reactant: COC(=O)C(O)(c1ccccc1)c1ccco1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)c1ccco1
Temperature: 25 °C

Procedure:
3.24 g (0.014 mols) of (Furan-2-yl)-hydroxy-phenylacetic acid methyl ester were dissolved in 85 ml of toluene. To this solution were added 2.08 g (0.016 mols) of 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane and 0.224 g (5.6 mmols) of HNa (60% dispersion in mineral oil). The mixture was refluxed with continuous removal of distillate and when necessary replacement with fresh toluene for 1.5 hours. The cooled mixture was extracted with 2N HCl acid, the aqueous layer washed with ethyl acetate, basified with K2CO3 and extracted with CHCl3. The organic layer was dried over Na2SO4 and evaporated. The oil obtained (3.47 g) crystallised after cooling at room temperature. This solid was suspended in hexane and filtered. The yield was 2.5 g (54%) of a mixture of diastereoisomers, mp: 140-142° C.; GC/MS [M]+: 327;
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(Cl)(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:22]3[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCNCC1
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1

Procedure:
A solution of 32.4 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in Example 5, in 300 ml of dimethyl sulfoxide, is stirred and heated at 140° for 6 hours with 12.8 g of 4-methylpiperidine and 35.8 g of anhydrous potassium carbonate, cooled and poured into water. The solid obtained is dissolved in chloroform and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-5-[4-methylpiperidin-1-yl]-6-nitrobenzothiazole melting at 116°-120°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (8.00 g), N-hydroxyphthalimide (4.13 g), potassium carbonate (7.05 g) and N,N-dimethylforrnamide (80 ml) was stirred at room temperature for 20 hours and water (800 ml) was added. The resultant crystals were filtered and washed with water to obtain N-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (10.1 g, yield 90%) as pale-brown crystals. m.p. 146-147° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[N:18][CH:17]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCCl.CC(O)=O>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)[CH:19]=[N:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cncc(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cncc(Cl)n2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
Sodium triacetoxy-borohydride (1315 mg, 6.2 mmol) was added to a solution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mmol) in 50 ml of DCE, 1 ml of HOAc was added and the mixture was stirred overnight at 50° C., followed by addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 6:1) to give 50 mg of (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 10%.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:6].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:4]=[C:3]3[C:15]([CH:16]=[CH:17][CH:18]=[CH:2]3)=[N:6]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(N(N)Cc2ccccc2Br)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2cc3ccccc3n2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-(4-Methoxyphenyl)-2H-indazole was prepared according to Song and Yee (Org. Lett. 2000, 2, 519). To a solution of N-(2-bromobenzyl)-N-(4-methoxyphenyl)hydrazine (298 mg, 0.97 mmol) in toluene (3.5 mL) were added palladium acetate (11 mg, 0.05 mmol), 1,1′-bis(diphenylphosphino)ferrocene (46 mg, 0.075 mmol) and sodium tert-butoxide (140 mg, 1.46 mmol). The vial was capped and the reaction was stirred at 90° C. overnight. After the reaction was allowed to cool, it was filtered through a pad of silica and concentrated to give the desired product. The reaction was assumed to be quantitative. LC-MS (C14H12N2O calculated 224) m/z 225 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[N:29]=[C:28]3[C:24]([N:25]=[C:26]([N:35]4[CH2:40][CH2:39][N:38]([C:41](=[O:47])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH2:37][CH2:36]4)[N:27]3[CH2:30][C:31]([F:34])([F:33])[F:32])=[C:23]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[N:22]=2)=[CH:17][N:16]=1)(C)(C)C>C1(C)C=CC=CC=1>[NH2:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[N:29]=[C:28]3[C:24]([N:25]=[C:26]([N:35]4[CH2:36][CH2:37][N:38]([C:41](=[O:47])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH2:39][CH2:40]4)[N:27]3[CH2:30][C:31]([F:33])([F:34])[F:32])=[C:23]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[N:22]=2)=[CH:17][N:16]=1
Reactant: CN(C)C(=O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(NC(=O)OC(C)(C)C)nc4)nc3n2CC(F)(F)F)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Trifluoroacetic acid (5 ml) was added to tert-butyl{5-[8-{4-[(dimethylamino)(oxo)acetyl]piperazin-1-yl}-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-yl}carbamate (148 mg, 0.22 mmol) and the resulting mixture was stirred for 30 minutes. Toluene was added and the solvent was evaporated under reduced pressure. Hydrochloric acid-methanol was added to the residue and the solvent was evaporated and dried to give the title compound (118 mg, 88%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[C:11](=[O:26])[NH:12][CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>O1CCOCC1>[C:1]1([CH:7]([N:9]2[C:10]3=[N:15][C:14]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:13][N:12]=[C:11]3[O:26][C:27]2=[O:28])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Nc1nc(-c2cccc3ncccc23)c[nH]c1=O)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(c1ccccc1)n1c(=O)oc2ncc(-c3cccc4ncccc34)nc21
Yield: 52 %

Procedure:
3-(1-Phenyl-ethyl)-5-quinolin-5-yl-3H-oxazole[4,5-b]pyrazin-2-one. 3-(1-Phenyl-ethylamino)-5-quinolin-5-yl-1H-pyrazin-2-one (50 mg, 0.15 mmol), 1,1′-carbonyldiimidazole (470 mg, 1.5 mmol), and dioxane (5 mL) were heated together in a pressure tube to 150° C. for 20 hours. The reaction was filtered through celite, rinsed with EtOAc, and then concentrated. The residue was purified via Biotage silica gel chromatography (0-100% ethyl acetate in hexanes). The product factions were concentrated and then triturated with ether to give a white solid, (28 mg, 52% yield). 1H NMR (400 MHz, CD3OD) δ 9.73 (dd, J=4.1, 1.8, 1 H), 9.11 (s, 1 H), 9.09 (d, J=8.2, 1 H), 8.93 (d, J=8.6, 1 H), 8.66 (m, 1 H), 8.58 (dd, J=7.2, 1.4, 1 H), 8.31 (m, 2 H), 8.26 (dd, J=8.6, 4.3, 1 H), 8.17 (m, 2 H), 6.43 (q, J=7.0, 1 H), 2.71 (d, J=7.0, 3 H); MS (ESI) m/z 369.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:32].[K+].[K+].OO.CO>CS(C)=O>[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:32])=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C#N)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 173.1 %

Procedure:
Using a method similar to Example 371, (±)-6-[2-methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile (compound of example 368) (0.246 g, 0.642 mmol), potassium carbonate (0.0429 g, 0.310 mmol), and 30% hydrogen peroxide Solution (aq) (0.220 mL, 1.94 mmol) in dimethylsulfoxide provide, after ion exchange chromatography (methanol→2 M ammonia/methanol), 0.223 g (87%) of the title compound as a while solid: high resolution mass spectrum (electrospray): m/z calc for C25H25N3O2 402.2182, found 402.2172; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.51 (d, 2H, J=8.3 Hz), 7.32-7.22 (m, 4H), 7.20-7.14 (m, 3H), 7.04 (d, 1H, J=8.8 Hz), 3.77 (s, 2H), 2.97 (ddd, 1H, J=3.4, 6.3, 13.2 Hz), 2.92-2.83 (m, 3H), 2.81-2.72 (m, 1H), 2.04-1.76 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([C:20]2[C:21]([F:41])=[C:22]([N:28](S(CCC)(=O)=O)[S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:23]=[C:24]([F:27])[C:25]=2[F:26])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([C:20]2[C:21]([F:41])=[C:22]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:23]=[C:24]([F:27])[C:25]=2[F:26])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccc(Cl)cc4)nc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccc(Cl)cc4)nc3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a N-(3-(3-(4-chlorophenyl)quinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.08 mmol, 1.0 eq.) in MeOH (5 mL) was added NaOH aqueous solution (1 N, 0.16 mL, 0.16 mmol, 2.0 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(3-(3-(4-chlorophenyl)quinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)propane-1-sulfonamide (25 mg, 60.2%). LRMS (M−H+) m/z calculated 518.1, found 518.0. 1H NMR (CDCl3, 400 MHz) δ 9.42 s), 8.44 (s, 1 H), 8.27-8.38 (m, 2 H), 8.14-8.16 (dd, 2 H), 7.73-7.76 (m, 1 H), 7.55-7.57 (dd, 2 H), 6.55 (s, 1 H), 3.14-3.18 (m, 2 H), 1.88-1.94 (q, 2 H), 1.06-1.10 (t, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(Cl)Cl.Cl.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40]Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Ba+2]
Solvent: ClCCl
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
0.2 g of triethylbenzylammonium chloride, 3 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one and 6.4 g of barium hydroxide octahydrate were added under vigorous stirring to 60 ml of methylene chloride and 10 ml of water. A solution of 3.2 g of 2-(dimethylamino)-ethyl chloride-hydrochloride in 5 ml of water was added dropwise to the above mixture during 5 minutes. Stirring was continued at room temperature for 1 hour and then at 40° for 24 hours. After cooling to room temperature the aqueous phase was separated and discarded and the methylene chloride was removed under vacuum. (Petroleum ether (40°-60°) was added to the viscous residue with induced crystallisation. The crystals obtained were filtered off and dried under vacuum to yield 3.7 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-5-(2'-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one; m.p.88°-90°; [α]D27 +169 (C=0.25, CH3OH).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].C(OC([N:15]1[C@H:19]([CH2:20][OH:21])[CH2:18][C@H:17]([O:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[NH:30][C:31]2[C:32]3[C:39]([CH3:40])=[C:38]([C:41](N)=[O:42])[S:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:3][O:4][C:41]([C:38]1[S:37][C:33]2[N:34]=[CH:35][N:36]=[C:31]([NH:30][C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[O:22][C@H:17]3[CH2:18][C@@H:19]([CH2:20][OH:21])[NH:15][CH2:16]3)[C:32]=2[C:39]=1[CH3:40])=[O:42]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CN[C@H](CO)C3)c2c1C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 4-[2-((3S,5S)-1-tert-butoxycarbonyl-5-hydroxymethyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (754 mg) in dichloromethane (10 ml). The reaction mixture was stirred for 4 h and a further aliqout of trifluoroacetic acid was added. The reaction mixture was stirred for 1 h again. The solvent was removed in vacuo. The mixture was diluted with dichloromethane and washed with 10% aq. K2CO3. The organic layer was concentrated and the residue was purified by flash column chromatography (silica gel, solvent: 100% dichloromethane→20:1:0,1 dichloromethane: MeOH: NH4OH)
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[BH4-].[Li+].S([O-])(O)(=O)=O.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O>[C:7]([O:11][C:12](=[O:13])[NH:14][CH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:18]([CH2:19][OH:20])[CH:17]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 78.6 %

Procedure:
At 0° C., ethyl chloroformate (1.93 ml, 20 mmol) was added to a solution of 3-(tert-butoxycarbonylaminomethyl)benzoic acid (5.0 g, 20 mmol) and triethylamine (3.33 ml, 24 mmol) in tetrahydrofuran (30 ml). The reaction mixture was stirred for 40 min at 0° C., and the formed precipitation was filtered off. The filtrate was cooled to 0° C. A 2.0 M solution of lithium borohydride in THF (25 ml, 50 mmol) was added. The reaction mixture was stirred for 16 h, while warming up to room temperature. Water was added carefully, until no gas was formed. A 10% solution of sodium hydrogensulphate (10 ml) was added. A saturated solution of sodium hydrogen carbonate (200 ml) was added. The mixture was extracted with ethyl acetate (200 and 100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane 1:1 as eluent, to give 3.73 g of (3-hydroxymethylbenzyl)carbamic acid tert butylester.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[ClH:29]>>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[Cl:29][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCCNCC2)cn1
Reactant: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Product: Clc1ccc(N2CCCNCC2)cn1
Reaction time: 8 h

Procedure:
1-(6-Amino-3-pyridyl)-homopiperazine (96 mg, 0.5 mmol) was solyed in conc. hydrochloric acid (2.0 ml). Sodium nitrite (45 mg, 0.65 mmol) was added at 0° C. The mixture was allowed to reach room-temperature and was stirred overnight. The mixture was poured out on water (20 ml) and was refluxed for 10 minutes. The mixture was made alkaline by adding aqueous sodium hydroxide (1.0 ml, 4 M). The mixture was extracted with ethyl acetate (3×10 ml). The product was isolated as an oil. Yield 50 mg (47%). The free base was converted to the corresponding fumaric acid salt. Mp. 165-167° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:34][C:35]1[CH:36]=[C:37]([CH:43]=[C:44]([CH2:46][N:47]2[CH:51]=[CH:50][N:49]=[CH:48]2)[CH:45]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CS(C)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:34][C:35]4[CH:36]=[C:37]([CH:43]=[C:44]([CH2:46][N:47]5[CH:51]=[CH:50][N:49]=[CH:48]5)[CH:45]=4)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)c1cc(CCl)cc(Cn2ccnc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(Cn2ccnc2)cc(Cn2cc(C3c4ccc(CC)cc4C=Cc4oc(C)nc43)c(=O)[nH]c2=O)c1

Procedure:
A solution of the product of example 3 step (vii) (2.5 g) in dry dimethylsulphoxide (30 ml) was treated with cesium carbonate (10 g) with stirring. After 20 min a solution of the product of step (ii) (1.5 g) in dimethylsulphoxide (10 ml) was added dropwise over 2 min. After 1.5 hours the reaction mixture was quenched with saturated brine and the product extracted into ethyl acetate. The organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure to leave a brown gum. Column chromatography eluting with 10% methanol in ethyl acetate containing 1% triethylamine gave the product as a glass.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].CC1(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]3)[CH:35]=2)OC1(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]4)[CH:35]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A 100-mL round-bottom flask was purged with nitrogen and then charged with 3,3-difluorocyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (300 mg, 0.70 mmol), tert-butyl 3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (487 mg, 1.39 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane complex (69 mg, 0.08 mmol), cesium carbonate (456 mg, 1.40 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture stirred overnight at 90° C. in an oil bath. After cooling to room temperature, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 8:1 ethyl acetate/petroleum ether) to afford 3,3-difluorocyclobutyl (S)-4-acetyl-7-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (300 mg, 79%) as a yellow oil. MS (ESI, pos. ion) m/z 546 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Br[CH2:13][S:14]([OH:17])(=[O:16])=[O:15].[Na]>O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][S:14]([OH:17])(=[O:16])=[O:15]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=S(=O)(O)CBr
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)COc1ccc(Cl)cc1Br
Yield: 68.3 %

Procedure:
To a solution of 75.0 g of 2-bromo-4-chlorophenol in 65 ml of water is added 16.0 g of sodium hydroxide and 100 g of bromomethanesulfonic acid, sodium salt. The procedure of Example 1, part B, is followed to give about 74.5 g of 2-bromo-4-chlorophenoxymethanesulfonic acid, sodium salt, m.p. above 315° .
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][N:19]=[C:18]([Cl:27])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:27])[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc(Cl)ncc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylate (797 mg, 2.00 mmol) in THF (10 mL), aq. 1N NaOH (10 mL, 10.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (720 mg).