Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]1[C:12]([CH3:15])=[N:13][N:14]=[C:9]1[CH2:8][CH2:7]2.Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:34])[C:31]=1[CH2:32][CH3:33].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:34])[C:31]=2[CH2:32][CH3:33])[CH:5]=[C:6]2[C:11]=1[N:10]1[C:12]([CH3:15])=[N:13][N:14]=[C:9]1[CH2:8][CH2:7]2
Reactant: CCc1c(F)cncc1Br
Reactant: Cc1nnc2n1-c1c(Cl)cc(B3OC(C)(C)C(C)(C)O3)cc1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(F)cncc1-c1cc(Cl)c2c(c1)CCc1nnc(C)n1-2
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 9-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (80-4; 0.717 g, 0.0020 mol) and 3-bromo-4-ethyl-5-fluoropyridine (0.423 g, 0.0020 mol) in the mixture of 1,4-dioxan (5 mL) and water (5 mL) was added sodium carbonate (0.66 g, 0.0062 mol). Reaction mass was purged with argon for the next 20 min. Catalyst Pd(dppf)2Cl2.dichloromethane (0.084 g, 0.0001 mol) was added and again purged with argon for 10 min and allowed to stirred at 90° C. for 4 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography followed by preparative HPLC (analytical conditions; column: ZORBAX XDB (150 mm×4.6 mm×3.5 μm), mobile phase (A): water, Mobile phase (B): MeOH, flow rate: 1.0 mL/min, gradient T/% B:0/20,6/25,25/75,27/20,30/20) to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 8.32 (s, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 2.94 (bs, 4H), 2.65-2.59 (m, 2H), 2.56 (s, 3H), 1.09-1.05 (t, J=7.6 Hz, 3H). MS (M+1): 343.2.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]1=[O:17].[NH2:18][C:19]1[N:24]=[C:23]([SH:25])[C:22]([C:26]#[N:27])=[C:21]([S:28][CH3:29])[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:18][C:19]1[N:20]=[C:21]([S:28][CH3:29])[C:22]([C:26]#[N:27])=[C:23]([S:25][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[C:3]2=[O:17])[N:24]=1
Reactant: CSc1nc(N)nc(S)c1C#N
Reactant: O=C1C(Br)CCN1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(SC2CCN(c3cccc(C(F)(F)F)c3)C2=O)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask was added 3-bromo-1-[3-(trifluoromethyl)-phenyl]-pyrrolidin-2-one (21) (308 mg, 1.0 mmol, 1.0 eq.), DMF (3.0 mL), 2-amino-4-mercapto-6-methylsulfanyl-pyrimidine-5-carbonitrile (198 mg, 1.0 mmol, 1.0 eq.), and potassium carbonate (207 mg, 1.5 mmol, 1.5 eq.). The reaction was stirred at RT overnight before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with 10% LiCl (20 mL, 2×), washed with brine, dried with Na2SO4, and concentrated to give crude product. Pure 2-amino-4-methylsulfanyl-6-[2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylsulfanyl]-pyrimidine-5-carbonitrile was precipitated out with 20:80 EtOAc:Hexanes, filtered, and dried under high vacuum (193 mg, 45%). LC/MSD (HP Series 1100 MSD): Expected MW: 425, Observed M+H, 426.1, Retention time: 1.60 min. ANALYTICAL HPLC: >98%, Retention time: 5.56 min (8 minute run). 1H-NMR (d6-DMSO): 8.20 (s, 1 H), 7.85 (d, 1H), 7.69 (t, 1H), 7.50 (d, 1H), 4.75 (t, 1H), 4.00 (dt, 2H), 2.72 (m, 1H), 2.40 (s, 3H), 2.39 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](OS(C)(=O)=O)([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][N:6]=1)[CH3:4].[CH3:22][Al](C)C.O>ClCCl>[CH3:14][O:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([CH3:22])([CH3:4])[C:2]([F:21])([F:20])[F:1])=[N:6][CH:7]=1
Reactant: C[Al](C)C
Reactant: COCOc1ccc(C(C)(OS(C)(=O)=O)C(F)(F)F)nc1
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(C(C)(C)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
1.7 g (4.13 mmol) methanesulfonic acid 2,2,2-trifluoro-1-(5-methoxymethoxy-pyridin-2-yl)-1-methyl-ethyl ester was dissolved in 20 ml dichloromethane. The reaction mixture was cooled to 0° C. where 2.065 ml (4.13 mmol) trimethylaluminum was added slowly. The reaction mixture was stirred at room temperature for 20 h. After that water was added slowly and the mixture was extracted 2 times with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel (EtOAc, heptane) to yield to afford 0.55 g of the pure title compound. LCMS (method L): tR=1.09 min, M+H=250.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54][C@@H:53]2[OH:61])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]>>[CH2:2]([O:61][C@H:53]1[CH2:54][C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:52]1[NH:51][C:35]1[C:34]([CH2:32][CH3:33])=[N:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])=[C:37]([CH2:49][CH3:50])[N:36]=1)[CH3:3]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a light yellow semi-solid. IR (liq.) 2971, 2934, 1609, 1562, 1480, 1391, 1294, 1243, 1206, 1184, 1171, 1161, 1119, 1091, 1054 cm−1; OAMS supporting ions at: ESI+ 432.1; MS (EI) m/z 431 (M+); HRMS (FAB) calcd for C27H33N3O2+H1 432.2651, found 432.2650. Anal. Calcd for C27H33N3O2: C, 75.14; H, 7.71; N, 9.74. Found: C, 74.86; H, 7.72; N, 9.67.
Reaction SMILES: [CH2:1]([CH:8]([C:12](=[O:14])[CH3:13])[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>ClCCl>[CH:1](=[C:8]([C:9](=[O:11])[CH3:10])[C:12](=[O:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(Cc1ccccc1)C(C)=O
Agent: BrBr
Solvent: ClCCl
Product: CC(=O)C(=Cc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution containing 6.3 g of 3-benzyl-2,4-pentanedione in 50 ml of dichloromethane was gradually added 5.3 g of bromine in 20 ml of dichloromethane under cooling (0°-5° C.). The solution was stirred for 10 min. at 0° C. and the solvent evaporated in vacuo. The residue was dissolved in 100 ml of pyridine and refluxed for 30 min. Pyridine was evaporated in vacuo, the residue was dissolved in dichloromethane and washed first with 6M hydrochloric acid and then with 2.6M NaOH. The solvent was evaporated and the residue distilled in vacuo. Bp 186°-188° C./16 mm, yield 1.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=[O:24])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)([OH:38])N.Cl([O-])=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]([OH:38])=[O:24])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)c1
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a stirred solution of the product from Example 151 (58 mg, 0.11 mmol) in dichloromethane (3 mL) and water (3 mL) at 0° C. was added sulfamic acid (44 mg, 0.44 mmol) and sodium chlorite (30 mg, 0.33 mmol). The reaction was allowed to attain room temperature with stirring over 3 hours, the layers separated and the aqueous layer extracted with further dichloromethane (5 mL). The combined organic layers were dried (MgSO4) and evaporated to leave a residue which was filtered through a plug of silica eluting with ether:dichloromethane:iso-hexane 1:1:3, then purified by column chromatography on silica eluting with ethyl acetate:dichloromethane 1:1 +1% acetic acid to afford the desired compound (40 mg).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: CSc1ccc(C(OC2CN(C(=O)NC(C)(C)C)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-trifluoromethyl-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) (1.28 mmol), tert-butyl isocyanate (1.28 mmol) and mp-carbonate (2.62 mmol/g, 3.85 mmol) using the procedure described for compound (10) (433 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:31]=[CH:32][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCCCc1ccc(N2CCNCC2)cc1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCCCc1ccc(N2CCN(C(=O)Nc3nc4ccccc4nc3OC)CC2)cc1
Yield: 65.4 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(4-butylphenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:6][CH2:5]1.[CH3:19][N:20]([CH3:38])[C:21]([C:23]1[N:32]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28](Cl)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][N:20]([CH3:38])[C:21]([C:23]1[N:32]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:5][CH2:6]4)=[CH:15][N:14]=3)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]
Reactant: Nc1ccc(N2CCN(CC(F)(F)F)CC2)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC(F)(F)F)CC4)cn3)nc2n1C1CCCC1
Temperature: 100 °C

Procedure:
A mixture of 5-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (158 mg, 0.607 mmol), 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (118 mg, 0.405 mmol), Pd2(dba)3 (18.5 mg, 0.020 mmol), BINAP (25 mg, 0.040 mmol) and sodium-tert-butoxide (70 mg, 0.728 mmol) in dioxane (3.5 mL) is degassed and heated to 100° C. for 1 h in a CEM Discover microwave. The reaction mixture is partitioned between dichloromethane and saturated NaHCO3 solution. The organic layer is separated and the aqueous layer extracted with further dichloromethane. The combined organics are ished with brine, dried (MgSO4), filtered and concentrated. The crude product is purified using silica gel chromatography (0 to 10% methanol/dichloromethane) to give 7-cyclopentyl-2-{5-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, which is purified further by trituration with acetonitrile (115 mg, 55%). MS (ESI) m/z 517.2 (M+H)+ (method A).
Reaction SMILES: [H-].[Na+].OC1C(C)=CC([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=3)=CC=1C.C1(=O)OC(=O)CC1.Cl>CN(C)C=O.C(OCC)(=O)C.C1C=CC=CC=1.O>[CH3:22][O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:19]2[CH3:20]
Reactant: COc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Agent: Cl
Agent: O=C1CCC(=O)O1
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2[nH]cc(C)c2c1
Temperature: 50 °C

Procedure:
In 30 ml of dry dimethylformamide was dissolved 0.88 g of 60% sodium hydride in oil. With ice cooling and stirring, a solution of 5.62 g of 2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-3-methylindole in dry dimethylformamide was added dropwise. After the addition, the mixture was stirred further for 1 hour. A solution of 2.2 g of succinic anhydride in dimethylformamide was added dropwise to the resulting solution. After the addition, the mixture was stirred at room temperature for 2 hours, then heated at 50° C. for 30 minutes, and further stirred at room temperature for 3 hours. The reaction solution was poured into water, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and extracted with aqueous sodium bicarbonate solution. The extracted aqueous layer was acidified with dilute hydrochloric acid, and extracted with 100 ml of ethyl acetate three times. The organic layers were washed and dried, and the solvent was evaporated under reduced pressure to give a crystalline residue. Rerrystallization of the residue from ethyl acetate/benzene gave 2-4-(3-carboxy- propionyloxy)-3,5-dimethylphenyl]-5-methoxy-3-methylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CCC1NCCc2c(F)cccc21
Product: CCC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[C:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](Nc2cccc(C)n2)C[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)[C@H](Nc1cccc(C)n1)C[C@H](C)N2C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of (2S,4R)-1-acetyl-2-methyl-N-(6-methyl-2-pyridinyl)-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 111) (0.226 g, 0.475 mmol) in tetrahydrofuran (THF) (5 mL) at room temperature was treated with TBAF (1N in THF, 0.570 mL, 0.570 mmol) and the resulting mixture was stirred at this temperature for 30 min then most of the solvent was removed in vacuo. The residue was partitioned between AcOEt and water and the layers were separated. The organic phase was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 10 G silica cartridge (gradient:5 to 25% (20% MeOH in DCM) in DCM) gave (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-(6-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine as an orange foam.
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)C=CC=CC=1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN1C(=O)CCC1>[C:20]([O:19][C:17](=[O:18])[NH:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:8]([NH:37][C@@H:34]2[CH2:35][CH2:36][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33]2)=[O:24])[CH2:15][CH2:14]1)([CH3:21])([CH3:22])[CH3:23]
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)CC1
Temperature: 100 °C

Procedure:
(4-tert-Butoxycarbonylamino-cyclohexyl)-carbamic acid phenyl ester (1 eq.) and (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) are dissolved in NMP and heated at 100° C. for 1 hour.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[CH:25][S:24][N:23]=1>ClCCl.C(OCC)(=O)C>[CH:1]1([NH:4][C:27]([C:26]2[C:22]([CH3:21])=[N:23][S:24][CH:25]=2)=[O:28])[CH2:3][CH2:2]1
Reactant: Cc1nscc1C(=O)O
Reactant: NC1CC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1nscc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
At -5° C., 3.7 g (65.0 mmol) of cyclopropylamine, 18.7 g (185.0 mmol) of methylmorpholine, 2.0 g (16.7 mmol) of dimethylaminopyridine and 43.5 g of a 50% strength solution of propanephosphonic anhydride in dichloromethane (=68.4 mol) were dripped one after the other into 7.2 g (50.0 mmol) of 3-methyl-isothiazole-4-carboxylic acid in 200 ml of dichloromethane, and the mixture was stirred for 12 hours at room temperature. The solvent was stripped off under reduced pressure, and the residue was taken up in 250 ml of ethyl acetate and extracted twice with saturated sodium bicarbonate solution and once with 5% strength citric acid solution, once with saturated sodium carbonate solution and once with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 84%; m.p.: 106°-108° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C([O-])([O-])=O.[Na+].[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:3]([C:2]([NH:1][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:6])[CH3:5])#[N:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-2-methylpropanenitrile in water an equimolar amount of Na2CO3 and a slight excess (1.1 eq) of benzylchloroformate were added, with an external cooling. Reaction mixture was stirred o/n at room temperature, extracted in EtOAc and the organic phase was washed with NaHCO3ss, dried (Na2SO4), filtered and concentrated. Product was obtained as a white solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1.[OH-].[K+].[I-].[K+].Cl[CH:17]([F:19])[F:18]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[F:18][CH:17]([F:19])[S:1][C:2]1[S:3][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1
Reactant: FC(F)Cl
Reactant: Sc1nnc(-c2cccs2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Sc1nnc(-c2cccs2)s1
Temperature: 40 °C

Procedure:
6.0 g of 2-mercapto-5-thienyl-1,3,4-thiadiazole and 45 ml of dioxan are added, while stirring, to a solution of 2.9 g of potassium hydroxide in 10 ml of water. After the addition of 0.2 g of potassium iodide and 0.1 g of tetrabutylammonium bromide the mixture is heated to 40° C. and, while stirring vigorously, a weak stram of chlorodifluoromethane is introduced for a period of 3 hours. The reaction mixture is then concentrated by evaporation in vacuo. The residue is taken up in methylene chloride and extracted by washing in succession with water and 1N sodium hydroxide solution. Evaporation of the solvent yields the title compound (recrystallised from cyclohexane) in the form of colourless crystals having a melting point of 63°-64° C.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH2:14]([N:21]1[CH2:30][CH2:29][C:28]2[N:27]=[C:26](Cl)[CH:25]=[CH:24][C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([O:36][C:37](=[O:40])[CH:38]=[CH2:39])([CH3:35])([CH3:34])[CH3:33]>O1CCOCC1.C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]([N:21]1[CH2:30][CH2:29][C:28]2[N:27]=[C:26](/[CH:39]=[CH:38]/[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)/C=C/c1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Tri-tert-butylphosphine (3.0 g, 15.28 mmol) was added to a solution of tris(dibenzylideneacetone)dipalladium (4.2 g, 4.63 mmol) in 1,4-dioxane (45 ml), under argon, and the solution stirred for 30 minutes at room temperature. This solution was then added to a mixture of 6-benzyl-2-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine (WO 9830560 Example 33b) (12 g, 46.3 mmol) and tert-butylacrylate (20.3 ml, 139 mmol) in triethylamine (45 ml), and the reaction was stirred under reflux for 17 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (300 ml) and water (300 ml) and this mixture filtered through Arbocel®. The pH of the mixture was adjusted to 8 using sodium bicarbonate, the phases separated, and the aqueous layer re-extracted with ethyl acetate (2×100 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The crude product was pre-adsorbed onto silica gel, and purified by column chromatography using an elution gradient of cyclohexane: ethyl acetate (84:16 to 66:34) to afford the title compound as an orange-red oil, (15.8 g).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[O:8])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[SH:29]>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[O:8])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc(Cl)cc1Cl
Product: O=C(c1cccc([N+](=O)[O-])c1)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1

Procedure:
Prepared according to the procedure described for example 18 from (5-chloro-4-nitro-2-thienyl)-(3-nitrophenyl)methanone (100 mg, 0.28 mmol) and 2,4-dichlorobenzenethiol (50 mg, 0.28 mmol). The title compound was obtained as a solid (35 mg, 28% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.52 (2H, m), 8.26 (1H, m), 8.24 (1H, m), 8.11 (1H, m) 8.04 (1H, m), 7.87 (1H, m), 7.74 (1H, m).