Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41]>O1CCCC1>[Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([O:25][C:39]([C:40]([OH:42])=[O:41])([CH3:44])[CH3:43])=[O:24])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)CC2
Reactant: CC(C)(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC(C)(C)C(=O)O)c(Cl)c1Cl)CC2
Temperature: 25 °C

Procedure:
(+)[(3,4-Dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetic acid (351 mg, 1 mmole) is dissolved in tetrahydrofuran (10 ml) and treated with 1,1'-carbonyldiimidazole (160 mg, 1 mmole) and the mixture stirred at room temperature for an hour. 2-Hydroxy-2-methylpropionic acid (105 mg, 1 mmole) is added and the mixture stirred for 18 hours at room temperature. The solvent is removed by evaporation in vacuo and the residue purified by column chromatography on silica gel using dichloromethane/tetrahydrofuran/acetic acid (100/2/1, v.v.v.) to give 1-carboxy-1-methylethyl (+)[(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]=[C:22]4[SH:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].S(OC)(O[CH3:33])(=O)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]=[C:22]4[S:26][CH3:33])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnnc4S)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N2CCN(c3ccc(-n4cnnc4SC)cc3)CC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 9 parts of 4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-4H-1,2,4-triazole-3-thiol, 2 parts of sodium hydroxide and 160 parts of methanol is stirred and warmed till all solid enters solution. Then there are added 3.3 parts of dimethyl sulfate and stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water. The precipitated product is filtered off and crystallized from 1-butanol, yielding 5.3 parts of 1-(4-methoxyphenyl)-4-{4-[3-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}piperazine; mp. 180° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:28]([N:33]([CH3:41])[C:34](=[O:40])[C@H:35]([CH:37]([CH3:39])[CH3:38])[NH2:36])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:26][CH3:27])[C@@H:13]([CH3:25])[C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:42]([O:46][C:47]([NH:49][C:50]1([C:54](O)=[O:55])[CH2:53][O:52][CH2:51]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[C:42]([O:46][C:47]([NH:49][C:50]1([C:54]([NH:36][C@H:35]([C:34]([N:33]([C@@H:28]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:26][CH3:27])[C@@H:13]([CH3:25])[C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:41])=[O:40])[CH:37]([CH3:39])[CH3:38])=[O:55])[CH2:51][O:52][CH2:53]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OC(C)(C)C)COC1)C(C)C
Reaction time: 16 h
Yield: 104 %

Procedure:
To #73 (100 mg, 0.174 mmol, 1 eq.) in dichloromethane (4 mL, 0.04) and N,N-dimethylformamide (0.5 mL) was added #71 (45.2 mg, 0.208 mmol, 1.2 eq.), followed by diisopropylethylamine (92 μL, 0.521 mmol, 3 eq.) and HATU (102 mg, 0.260 mmol, 1.5 eq.). After 16 hours, the reaction was concentrated in vacuo and the residue was taken up in ethyl acetate (6 mL) and washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by reverse phase chromatography (Method C) to give #74 (140 mg), which was used in the next step without further purification. LC-MS: m/z 774.7 [M+H+], 796.6 [M+Na+], retention time=0.91 minute.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]#[N:33])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:31])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
2.50 g (5.29 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-2-yl)propanoate (mixture of racemic diastereomers) in 60 ml of dichloromethane and 15.3 ml (198 mmol) of TFA were reacted according to General Method 6A. Yield: 2.20 g (71% of theory)
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:10][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1.CO>[C:26]([O:20][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][C:9]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[O:12][C:13]=2[CH:19]=[CH:18][CH:17]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cc2nc3c(O)cccc3o2)cc1OC1CCCC1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(Cc2nc3c(OC(C)=O)cccc3o2)cc1OC1CCCC1
Yield: 53 %

Procedure:
A solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-4-hydroxybenzoxazole (200 mg) and acetyl chloride (84 μl) in pyridine (6 ml) was stirred at room temperature, under nitrogen, for 3 hours. The reaction mixture was diluted with methanol (20 ml) and evaporated in-vacuo to yield a yellow solid. The solid was purified by flash chromatography (SiO2; dichloromethane; methanol (50:1)) and crystallized from ether/petroleum ether to yield the title compound (119 mg, 53%) as a white crystalline solid (mp 65-67° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.Cl>ClCCl>[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]2)=[O:14])=[CH:11][CH:10]=1
Reactant: OC1CCCNC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCCC(O)C1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 3-hydroxypiperidine (0.6 g, 5.93 mmol), 4-fluorobenzoic acid (0.83 g, 5.93 mmol), HOBT (0.8 g, 5.93 mmol), EDCI.HCl (1.7 g, 8.9 mmol) and dry triethylamine (1.66 mL, 11.86 mmol) in dry dichloromethane (30 mL) was kept under stiffing overnight at ambient temperature, under nitrogen atmosphere. HCl 1N (30 mL) was then added and the phases separated. The organic layer was washed with HCl 1N (30 mL), with NaOH 1N (30 mL×2 times), then with water (30 mL). Evaporation of the organic solvent afforded (4-fluoro-phenyl)-(3-hydroxy-piperidin-1-yl)-methanone as a white oil (0.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and decanoic acid to yield (3aR,4S,7aR)-4-decanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT1.70 min; UPLC Method I
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].[C:6]1([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(C(O)=O)(F)(F)F>[C:6]1([CH:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:2][CH2:3][CH2:4][NH2:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCS
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCSC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 2-mercaptoethylamine hydrochloride (12.058 g, 0.106 mol) and diphenylmethanol (20.062 g, 0.109 mol) in CF3CO2H (180 ml) was stirred at room temperature for 5.5 hours, then evaporated to a brownish/orange oil. Ether (500 ml) and 2N NaOH (200 ml) were added. The ether layer was washed with water (3×100 ml), saturated aqueous NaCl (100 ml), dried (MgSO4) and most of the ether removed in vacuo. The solution was cooled to -10° giving white crystalline compound (XXVI). This material was filtered, washed with cold ether and dried in vacuo (18.323 g, 71%). The volume of the combined washing and filtrate was reduced and cooled (-10° C.) giving a second crop, combined yield 20.479 g (84%), mp 74° .
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[C:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[N:13]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].[P:30]([O-:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>C(Cl)(Cl)(Cl)Cl>[P:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]2[C:10]([N:11]=1)=[C:9]([Cl:8])[N:17]=[CH:16][N:15]=2)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:37]
Reactant: CC(C)(C)Cn1c(-c2ccccc2O)nc2c(Cl)ncnc21
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)Oc1ccccc1-c1nc2c(Cl)ncnc2n1CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.1 mmol) was added slowly to an ice-cooled solution of. 6-chloro-N9-neopentyl-8-(2-hydroxyphenyl)purine (1 mmol) and diethyl phosphite (1 mmol) in carbontetrachloride. The reaction was stirred at room temperature overnight. Triethylamine hydrochloride was precipitated as a white solid mass. Extraction and chromatography gave diethyl 2-(6-Chloro-N9-neopentylpurin-8-yl)phenyl phosphate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:26][C:27]1[CH:28]=[C:29]([NH2:42])[CH:30]=[CH:31][C:32]=1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]>O1CCCC1>[F:26][C:27]1[CH:28]=[C:29]([NH:42][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])[CH:30]=[CH:31][C:32]=1[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(O)(C(F)(F)F)C(F)(F)F
Temperature: 45 °C
Yield: 13.3 %

Procedure:
To a solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.26 g, 5.9 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated to 45° C. in an ultrasound bath for 30 minutes, then 3-fluoro-4-phenylsulfonylbenzeneamine (1.35 g, 5.4 mmol) was added in one portion. The reaction mixture was heated at 65° C. in the ultrasound bath for 30 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue partitioned between water and ethyl ether. The aqueous layer was extracted with ethyl ether (2×50 mL), and the combined ether portions were dried (MgSO4) and concentrated in vacuo to an off-white solid. The solid was dissolved in ethyl ether, treated with HCl/ethyl ether and filtered to remove unreacted 3-fluoro-4-phenylsulfonylbenzeneamine. The filtrate was concentrated in vacuo, and the resulting solid recrystallized from ethyl ether/hexane to yield the title propanamide as a white solid (0.32 g, 13%); mp 188°-189° C. 1H-NMR (250 MHz, d6-DMSO): 7.62-7.84 (m, 4H, aromatic) 7.91-7.94 (m, 3H, aromatic) 8.03-8.09 (m, 2H, aromatic) 9.60 (s, 1H, NH). MS (CI, CH4): 446 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.OB(O)[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=[O:33].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.C(Cl)Cl.O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=[C:2]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([OH:34])=[O:33])[C:3]=2[CH:17]=[CH:16][C:15]1=[O:18]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
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: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2nc(NC(CO)CO)nc3c2ccc(=O)n3-c2ccc(F)cc2F)c1
Yield: 90.8 %

Procedure:
A mixture of 4-chloro-8-(2,4-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (20 mg, 0.047 mmol), 3-(dihydroxyboranyl)benzoic acid (11.8 mg, 0.07 mmol), K2CO3 (20 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium (2 mg, 0.0017 mmol), dioxane (1.2 ml), and water (0.4 ml) was heated in a sealed microwave vessel at 150 degrees for 10 min. The cooled solution was treated with DCM (3 ml), passed through a hydrophobic frit directly onto a silica cartridge (2 g). The cartridge was eluted with EtOAc followed by EtOAc/MeOH (9:1) to provide the title compound as a brown solid (20 mg, 80%) LC-MS m/z 469 (M+H)+ retention 2.73 min.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH3:13][NH2:14]>C1COCC1.CCOC(C)=O>[CH3:13][NH:14][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(CNC)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of ethyl 2-bromomethylthiazole-4-carboxylate (4.25 g, 17 mmol) in THF (50 ml) was added to a solution of methylamine in THF (2M, 30 ml, 60 mmol) drop-wise while cooling to −10° C. The mixture was allowed to warm to room temperature and stirred for a further 30 min. The mixture was diluted with EtOAc and washed with 0.3N potassium hydrogen sulphate solution and brine. The organic phase was dried and reduced to yield ethyl 2-(methylaminomethyl)thiazole-4-carboxylate (3.06 g, 70%) as an orange oil which was used without further purification.
Reaction SMILES: [S:1]([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)C=[CH:13]1.CCOCC>C(Cl)Cl>[CH3:2][S:1][C:3]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][CH:13]=1
Reactant: CSC
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CSc1c[nH]c2ccccc12
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 98.6 %

Procedure:
Me2S (955 μL, 13 mmol) was added to a solution of N-chlorosuccinimide (NCS, 1.47 g, 11 mmol) in DCM (80 mL) at 0° C., and stirred under N2 for 35 min. A solution of indole (1.17 g, 10 mmol) in DCM was added slowly, stirring at 0° C. for 2 h. While still cold, Et2O was added, and the white gum that formed was filtered off, dried under vacuum for 1.5 h, and stored at RT overnight. The intermediate was dissolved in DMSO, and the mixture heated to 100° C. under vacuum for 25 min. The product was poured into water, extracted with Et2O, and concentrated to dryness to yield 3-methylsulfanyl-1H-indole (1.609 g, 98.6% yield).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C([O-])(=O)C.[Na+]>O.CC(C)=O>[F:24][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc2)S1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
7 g (18.7 mmole) of 4-[2-(4-formylphenoxy)ethyl]phenyl trifluoromethanesulfonate, 2.74 g (23.4 mmole) 2,4-thiazolidinedione and 3.8 g (46.8 mmole) sodium acetate were mixed and heated under vacuum to 140° C. when it melted. It was kept at 140° C. for 20 minutes and thereafter taken off the heat, water:acetone (2:1) was added, the formed crystals were filtered off and recrystallization in dichloromethane gave 2.09 g (yield 24%) 5-(4-[2-(4-trifluoromethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:15]>CN1C(=O)CCC1>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([NH:27][C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=2)[CH2:25][CH2:26]1)[CH3:15]
Reactant: Cc1ccc2nc(Cl)nc(N)c2c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CN1CCCC1=O
Product: CCOc1cc(CN2CCC(Nc3nc(N)c4cc(C)ccc4n3)CC2)ccc1OC
Yield: 47 %

Procedure:
A solution of 2-chloro-6-methyl-quinazolin-4-ylamine (29.1 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in NMP (2 mL) was heated by microwave irradiation to 220° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 29.7 mg (39%) of the title compound. MS (ISP): 422.5 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:9])=[C:6]([Br:8])[N:7]=1.[Br-].C([O:14][C:15](=O)[CH2:16][CH2:17][Zn+])C>C1COCC1.O>[Br:8][C:6]1[N:7]=[C:2]2[CH2:17][CH2:16][C:15](=[O:14])[NH:10][C:3]2=[N:4][C:5]=1[Cl:9]
Reactant: Nc1nc(Cl)c(Br)nc1Br
Reactant: CCOC(=O)CC[Zn+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCc2nc(Br)c(Cl)nc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 3,5-dibromo-6-chloropyrazin-2-amine (step 1) (1.0 g, 3.48 mmol) and bistriphenylphosphinepalladium(II)chloride (0.122 g, 0.174 mmol) in THF (15 ml) under nitrogen was treated with (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (15.31 ml, 7.66 mmol) and the mixture was stirred at room temperature for 3 hours. A further portion of (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (7.5 mL, 3.8 mmol) was added and stirring continued for 1.5 hours. More (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (3.8 mL, 1.9 mmol) was added and the mixture was stirred at RT for 65 hours. The mixture was diluted with water (10 ml) and concentrated in vacuo. The residue was diluted with EtOAc (100 ml) the emulsion was filtered through Celite® (filter material). The phases were separated and the aqueous portion was extracted with EtOAc (50 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc (˜10 ml) to afford the title compound as yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:11]([NH2:15])(=[O:14])[CH:12]=[CH2:13].C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(=O)([O-])O.[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2](/[CH:13]=[CH:12]/[C:11]([NH2:15])=[O:14])[C:7]=2[CH:8]=[CH:9]1
Reactant: Clc1nccc2occc12
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: NC(=O)/C=C/c1nccc2occc12
Temperature: 140 °C
Reaction time: 16 h
Yield: 41.5 %

Procedure:
A mixture of 4-chlorofuro[3,2-c]pyridine (1.00 g, 6.51 mmol), acrylamide (694 mg, 9.77 mmol), sodium acetate (641 mg, 7.81 mmol), tetrabutylammonium bromide (2.31 g, 7.16 mmol), tri-o-tolylphosphine (396 mg, 1.30 mmol) and palladium(II) acetate (146 mg, 0.65 mmol) in N,N-dimethylformamide (20 mL) was stirred at 140° C. for 16 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (508 mg, yield 41%).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C:6]1[N:7]([C:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][NH:33][C:32]3=[O:36])[CH2:27][CH:28]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:22])=[CH:10][CH:9]=2>[Pd].C(O)C>[CH3:5][C:6]1[N:7]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][NH:33][C:32]3=[O:36])[CH2:27][CH2:28]2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)=[CH:12][C:11]([CH3:22])=[CH:10][CH:9]=2
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C1=CCN(CCN2CCNC2=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C1CCN(CCN2CCNC2=O)CC1
Temperature: 25 °C

Procedure:
Ammonium formate (12 g) was added in small portions during 18 h to a refluxing mixture of 2,5-dimethyl-3-(4-fluorophenyl)-1-[1-[2-(imidazolidin-2-on-1-yl)ethyl]1,2,3,6-tetrahydropyridin-4-yl]-1H-indole 6a (1.9 g), 5% palladium on activated carbon (1 g) and ethanol (50 ml). The reaction mixture was cooled to room temperature and the solvents were evaporated in vacuo. After addition of water the mixture was made alkaline with concentrated NaOH and extracted with ethyl acetate (2×50 ml).The combined organic phases were dried (Na2SO4) and the solvents were evaporated in vacuo. This afforded the title compound which crystallized from diethyl ether. Yield 0.2 g, mp 188°-190° C.