Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C@@:3]([OH:8])([CH3:7])[C:4](O)=[O:5].CC(N(C)C)=O.S(Cl)(Cl)=O.[C:19]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[CH3:28])#[N:20]>C1COCC1>[Br:1][CH2:2][C@@:3]([OH:8])([CH3:7])[C:4]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:19]#[N:20])=[C:22]([CH3:28])[CH:23]=1)=[O:5]
Reactant: Cc1cc(N)ccc1C#N
Reactant: C[C@](O)(CBr)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
(2R)-3-Bromo-2-hydroxy-2-methylpropionic acid (1.52 g, 8.3 mmol) was dissolved in 35 ml of dry THF and 0.5 ml of dry DMA was added. Solution was cooled to 0° C. and thionyl chloride (0.8 ml; 10.8 mmol) was added dropwise. The solution was allowed to heat up to room temperature and stirred for 2 hours at room temperature. 4-Cyano-3-methylaniline (1.07 g, 8.1 mmol) was added in 5 ml of dry THF and reaction refluxed for 2 hours. THF was evaporated, the residue dissolved in 40 ml of CH2Cl2 and washed with 50 ml of 1% NaHCO3 and then with 4×25 ml of water. The organic phase was evaporated and residue was dried under reduced pressure at 40° C. overnight to give 2.24 g of crude product which was crystallized from 5 ml of toluene (75° C. then cooled to room temperature and to 0° C.), filtered and washed with 5 ml of ice cold toluene. The precipitate was dried under reduced pressure overnight at 40° C. to give 1.54 g of the product.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9](=[O:18])[NH:8][C:7]1=[O:19]>C1COCC1>[O:19]=[C:7]1[NH:8][C:9](=[O:18])[C:10]([C:12]2[N:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][N:6]1[CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CCn1cc(-c2cccnn2)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: O=CCCn1cc(-c2cccnn2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
1-(3,3-Dimethoxy-propyl)-5-pyridazin-3-yl-1H-pyrimidine-2,4-dione (Prep122, 200 mg, 0.68 mmol) was dissolved in THF (5 ml) and then 2N HClaq (1 ml) was added. The solution was stirred at room temperature for 1 hour. The solvent was removed under vacuum at room temperature and the residue was lyophilized to give 185 mg of the title compound as hydrochloride salt (95% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[CH3:15][NH:16][C:17]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1)=[O:18]>>[CH3:15][NH:16][C:17]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH:14][C:12]2[CH:11]=[CH:10][C:9]3[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]=3[CH:13]=2)[N:26]=1)=[O:18]
Reactant: CCN1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)ccc21

Procedure:
3-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide was prepared from 9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 308c. Product isolated as a tan solid (124 mg, 60%). m.p.=199-201° C.; LCMS (m/e) 459 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.59 (s, 1H), 9.26 (s, 1H), 8.51-8.42 (m, 1H), 8.22 (d, 1H, J=4.8 Hz); 8.20 (s, 1H), 7.71 (d, 1H, J=5.3 Hz), 7.25 (s, 1H), 7.11 (d, 1H, J=9.34 Hz), 6.81 (d, 1H, J=8.8 Hz), 4.03 (t, 2H, J=5.3 Hz), 3.17 (q, 2H, J=7.0 Hz), 3.11 (t, 2H, J=5.0 Hz), 2.78 (d, 3H, J=4.3 Hz), 1.96-1.86 (m, 2H), 1.13 (t, 3H, J=7.0 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:13][C:14]([N:16]([CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15])[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:33]
Reactant: Cc1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2C)c1
Yield: 134.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(2-methylphenyl)acetamido]-N-methyl-N-phenylacetamide (1.2 g) and 3-methylphenyl isocyanate (1.3 g), and after recrystallisation in ethyl acetate, 2-{N-(2-methyl-phenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (2.3 g), m.p. 193° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N)(=[S:12])C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[S:12])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(Cl)cc1
Yield: 70.4 %

Procedure:
A mixture of 55.03 g of 4-chlorobenzonitrile, 75.13 g of thioacetamide and 600 ml of dimethylformamide was saturated with dry hydrogen chloride gas while being chilled in an ice bath. The mixture was then distilled slowly on an oil bath at 100° C. When the liquid had been removed, aqueous sodium bicarbonate was added. The solid was collected and recrystallized from toluene, giving 48.35 g of 4-chlorothiobenzamide as yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[CH:29]=4)[O:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1>>[CH3:34][O:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:35][CH3:36])[O:24][CH:23]=[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:8]3[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:11]=[CH:10][CH:9]=3)[CH2:13][CH2:14]1)[C:31]2=[O:32]
Reactant: CC(=O)Cl
Reactant: COc1cc2occ(CCCCN3CCN(c4cccc(N)c4)CC3)c(=O)c2cc1OC
Product: COc1cc2occ(CCCCN3CCN(c4cccc(NC(C)=O)c4)CC3)c(=O)c2cc1OC

Procedure:
In a similar manner to Example 13, but using acetyl chloride and 3-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-6,7-dimethoxychromen-4-one obtained in Example 12, N-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-acetamide is obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH:36]([CH3:38])[CH3:37])[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a light yellow foam (33%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>O1CCCC1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Yield: 92 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) and 0.5 g of triethylamine in 30 ml of tetrahydrofuran is added dropwise a solution of p-fluorophenylsulfonyl chloride in 10 ml of tetrahydrofuran over a 15 minute period. After complete addition, the resultant mixture is stirred for 1 hour at room temperature. The resulting mixture is filtered and the white solid is washed with more tetrahydrofuran and dried. This is re-crystallized from methanol/methylene chloride to give 2.5 g (92%) of white crystalline 1-[(4-fluorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 251°-253° C.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].N12CCCN=C1CCCCC2.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(OCC)(=O)C>C1COCC1>[CH3:20][C:19]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 10.0 g of methyl isocyanoacetate, 15.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 133 ml of anhydrous THF was cooled to 0° C., and a solution of 10.2 g of acetic anhydride in 33 ml of THF was added dropwise over 15 minutes. The mixture was stirred overnight at room temperature and stripped of solvent. The residue was mixed with 250 ml of ethyl acetate, the mixture was washed with water, dried (MgSO4), filtered and stripped of solvent. The residue was chromatographed on silica gel with a 1:1 v:v ethyl acetate/hexane mixture as eluent. The middle fractions gave methyl 5-methyl-4-oxazolecarboxylate (4A) as a white solid, m.p.: 46.5°-47.0° C.
Reaction SMILES: CC1C=C(C2C=CC(OC(F)(F)F)=CC=2)SC=1CO.[F:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[S:35][C:34]([CH2:36][O:37][Si](C(C)C)(C(C)C)C(C)C)=[C:33]([CH3:48])[CH:32]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[S:35][C:34]([CH2:36][OH:37])=[C:33]([CH3:48])[CH:32]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2F)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2F)sc1CO

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of {{3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol (intermediate 118) using ({5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane (intermediate 123).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[CH3:12][CH2:13][O:14]C(C)=O.[NH4+].[OH-]>C(Cl)Cl.CO>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]([NH:11][C:13](=[O:14])[CH3:12])[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: NC1CCOc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H]1CCOc2cccnc21
Reaction time: 2 h

Procedure:
Following the general procedure, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (243 mg, 1.62 mmol), CALB (73 mg) and EtOAc (6.0 mL) were stirred for 2 hours. The conversion determined from 1H NMR by integration of the peaks at 7.93 ppm and 8.16 ppm was 50% (CHNH2 and CHNHAc signals were not distinct). Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:10 NH4OH:MeOH:CH2Cl2 furnished the (R)—N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide ((145 mg, 47%) in 98% ee (chiral GC method: 140° C. for 16 min, ramp rate 5° C./min to 160° C., hold at 160° C. for 50 min, (S)-enantiomerrt=41.5 min, (R)-enantiomerrt=40.9 min); [α]D=−69° (c 1.45, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.91–2.00 (m, 1H), 1.97 (s, 3H), 2.47–2.57 (m, 1H), 4.18–4.22 (m, 2H), 4.85–4.92 (m, 1H), 6.97 (m, 2H), 7.24 (br s, 1H), 7.93–7.95 (dd, 1H, J=1.8, 3.9 Hz); 13C NMR (CDCl3) δ 23.3, 28.9, 47.2, 64.4, 124.3, 124.7, 141.3, 141.7, 152.0, 170.9; MS m/z: 215 (M+Na+). The unreacted (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (was isolated in 43% yield (104 mg) and 99% ee ((S)-enantiomerrt=14.7 min, (R)-enantiomerrt=15.6 min); [α]D=−13° (c 0.72, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 1.84 (br s, 2H), 1.90–2.01 (m, 1H), 2.24–2.34 (m, 1H), 4.12 (dd, 1H, J=5.7, 6.9 Hz), 4.18–4.26 (m, 1H), 4.28–4.36 (m, 1H), 7.06–7.13 (m, 2H), 8.15 (dd, 1H, J=1.8, 3.6 Hz); 13C NMR (CDCl3) δ 31.5, 47.8, 64.2, 123.8, 124.5, 142.1, 147.0, 151.1; MS m/z: 151.0 (M+H+), 134.0 (M−NH2); Anal. Calc. for C8H10N2O.0.1H2O: C, 63.22; H, 6.76; N, 18.43. Found: C, 62.99; H, 6.81; N, 18.22.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([OH:20])=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([O:20][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCCOCOc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 96 h
Yield: 92.3 %

Procedure:
To a stirred solution of 2′-methoxyethoxymethoxy-[1,1′;3′,1″]terphenyl-5′-ol (0.240 g, 0.685 mmol) in DMF (10 mL) at room temperature was added K2CO3 (0.123 g, 0.890 mmol) followed by dropwise addition of 1-bromobutane (0.147 mL, 1.37 mmol). The reaction mixture was then heated to 60° C. After 4 days at this temperature, the resulting solution was diluted with H2O (10 mL) and excess EtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat. aq. NaHCO3 (10 mL), and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (20% EtOAc/petroleum ether) to afford the product (0.257 g, 92%) as a solid; 1H NMR (CDCl3) δ 0.97 (t, J=8.1 Hz, 3H), 1.46–1.57 (m, 2H), 1.72–1.82 (m, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.95 (t, J=5.6 Hz, 2H), 3.17 (s, 3H), 3.99 (t, J=6.9 Hz, 2H), 4.37 (s, 2H), 6.87 (s, 2H), 7.28–7.46 (m, 6H), 7.58 (d, J=7.5 Hz, 4H); mass spectrum [(+) ESI], m/z 429 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:25])[C:15]3[S:19][C:18]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1.CCO.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:25])[C:15]3[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(N(C)Cc2ccc3nc(C)[nH]c(=O)c3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1nc2ccc(CN(C)c3ccc(C(=O)O)s3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 62.9 %

Procedure:
A 25 mL 3-necked flask equipped with a condenser, a thermometer, and a magnetic stirrer was charged with 0.20 g of ethyl 5-(((3,4-dihydro-2-methyl-oxo-6-quinazolinyl)methyl)methylamino)-2-thiophene caboxylate, 6 mL of EtOH, and 6 mL of 1N aqueous NaOH. The resulting solution was stirred under nitrogen at RT for 25 min and then at 55° C. for 2 h. Analysis by tlc (SiO2, 95:5 CH2Cl2) indicated no remaining starting material and a new component at Rf=0.06. The solution was cooled to RT and subjected to rotary evaporation to remove EtOH. The remaining solution was diluted with 10 mL of water and acidified to pH=3.5 by addition of 1N aqueous HCl. A tan precipitate formed which was collected by centrifugation, washed with four cycles of aqueous suspension centrifugation-decantation, and lyophilized to afford 0.116 g (63%) of 5-(((3,4-dihydro-2-methyl4-oxo-6-quinazolinyl)methyl)methylamino)-2-thiophene-carboxylic acid as a white powder, m.p. 195° C. (dec).
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14](Br)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(O)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14]([C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(c1nc(Br)cs1)N1C2CCC1COC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1C2CCC1COC2
Temperature: 92.5 °C
Yield: 51.9 %

Procedure:
To a solution of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(4-bromothiazol-2-yl)methanone (Step-1 of compound 68, 0.35 g, 1.15 mmol) in a mixture of toluene:ethanol (2.5 ml: 7.5 ml) were added (4-chlorophenyl) boronic acid (0.2 g, 1.27 mmol) and potassium carbonate (0.34 g, 2.42 mmol) at 25° C. in a tube, nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06 mmol) under nitrogen, tube was sealed and reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethanol (2×20 ml). The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 51.7%). MS: m/z 335 (M+1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.Br[CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CBr
Reactant: COc1ccc(C=O)cc1O
Product: COc1ccc(C=O)cc1OCC(C)C

Procedure:
The title compound was prepared by reaction of isovanillin with 1-bromo-2-methyl propane as described in WO 04/000 806 A1 (Elbion AG).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1>CCCCCC>[F:28][C:25]1[CH:26]=[CH:27][C:21]2[S:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[CH:14][CH:15]=3)=[N:23][C:22]=2[CH:24]=1
Reactant: CCOP(OCC)OCC
Reactant: Fc1ccc2sc(-c3ccc(CBr)cc3)nc2c1
Solvent: CCCCCC
Product: CCOP(=O)(Cc1ccc(-c2nc3cc(F)ccc3s2)cc1)OCC
Temperature: 25 °C
Yield: 82.2 %

Procedure:
Triethyl phosphite (50.0 g) was added to 31.0 g of 2-(4-bromomethylphenyl)-5-fluorobenzothiazole, and the mixture was reacted at 150° to 160° C. for 15 minutes under a stream of nitrogen. The reaction mixture was allowed to cool to room temperature, and 100 ml of n-hexane was added. The precipitated crystals were collected by filtration and dried to give 39.0 g of crude crystals. Recrystallization from a mixture of ethyl acetate and cyclohexane gave 30.0 g of the captioned compound as colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH:10]1([CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3][C:2]=2[NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:11][CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1ccc(OCC2CC2)c(N)c1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OCC2CC2)c(NS(C)(=O)=O)c1
Yield: 94.3 %

Procedure:
To a solution of crude methyl 2-(3-amino-4-(cyclopropylmethoxy)phenyl)acetate (theoric 4.74 mmol) in pyridine (50 ml), methanesulfonyl chloride (0.406 ml, 5.10 mmol) was added, and the mixture was reacted for 3 hours at RT. The solvent was evaporated to dryness, and the residue was partitioned between EtOAc and HCl 1N; the aqueous phase was extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. The solvent was removed under vacuum affording methyl 2-(4-(cyclopropylmethoxy)-3-(methylsulfonamido)phenyl)acetate (1.4 g, 4.47 mmol, 94.3% yield over 3 steps, MS/ESI+ 313.9 [MH]+). This intermediate was used without any additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2Cl.[OH:20][C@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:27]1[CH2:26][CH2:25][N:24]([C:22](=[O:23])[C@H:21]([OH:20])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:29][CH2:28]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(Br)cc23)CC1
Yield: 36.4 %

Procedure:
A solution of 6-bromo-4-chloro-2-(2-hydroxyphenyl)quinazoline (75 mg, 0.22 mmol), (R)-2-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one (60 mg, 0.3 mmol), triethylamine (42 μL, 0.3 mmol), and CH2Cl2 (2 mL) was stirred at room temperature overnight. After diluting with CH2Cl2, the reaction mixture was washed with H2O, dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography using 0-10% MeOH/CH2Cl2 to give (R)-1-{4-[6-bromo-2-(2 hydroxyphenyl)-quinazolin-4-yl]-piperazin-1-yl}-2-hydroxy-4-methyl-pentan-1-one (40 mg, 36%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]=O.Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.[Cl-].[Na+].O.ClCCl.O>[OH:22][CH:20]1[CH2:21][N:18]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:19]1
Reactant: O=CCc1ccccc1N1CCCCC1=O
Reactant: OC1CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCCN1c1ccccc1CCN1CC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.7 %

Procedure:
To [2-(2-oxopiperidin-1-yl)phenyl]acetaldehyde a3-1 (1.32 g, 6.09 mmol, 1 eq) in methanol (50 ml) is added azetidin-3-ol hydrochloride al 1-0 (0.76 g, 6.96 mmol, 1.14 eq). After stirring at room temperature for approximately 30 minutes, acetic acid (522 μl, 9.13 mmol, 1.5 eq), then NaBH3CN (1.15 g, 18.26 mmol, 3 eq) are added. The reaction mixture is stirred overnight at room temperature, then filtered and loaded on an ion exchange acidic resin cartridge prewashed with methanol. The cartridge is then washed with approximately 3 column volumes of methanol, then eluted with 3 column volumes of 1M ammonia in methanol. This eluate is evaporated to dryness. To the residue obtained is added water (50 ml) and dichloromethane (50 ml). After vigorous shaking and addition of brine, the 2 phases are separated. The organic phase is washed with water (50 ml). The aqueous phases are pooled and washed 3 times with iPrOH/CH2Cl2 (25 ml/50 ml). The organic phases are combined, evaporated to dryness to give 212.6 mg of 1-{2-[2-(3-hydroxyazetidin-1-yl)ethyl]phenyl}piperidin-2-one a11-1 (212.6 mg, 0.775 mmole if assumed pure, 12.7% yield), which is used in next step without any further purification.