Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:49])[C:20]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:21][C:22]=3[C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[N:30][CH:31]=3)[C:17]2=[O:50])=[C:13]([CH3:51])[CH:12]=[C:11]([CH3:52])[N:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:49][C:19]1[C:20]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:21][C:22]([C:26]2[CH:31]=[N:30][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[C:23]2[C:18]=1[C:17](=[O:50])[N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:52])=[CH:12][C:13]=1[CH3:51])[CH2:25][CH2:24]2
Reactant: Cc1cc(C)c(CN2CCc3c(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3c(-c4ccc(N5CCNCC5)nc4)cc(OC(C)C)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
A mixture of tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate (77f, 46 mg, 0.063 mmol) in TFA (2 mL) was stirred at room temperature for 3 hours. After concentrating volatiles under vacuum, the resulting residue was partitioned between ethyl acetate (30 mL) and sodium bicarbonate (30 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1×30 mL). The combined organic phases were dried over sodium sulfate, concentrated under vacuum, and purified by prep HPLC to give the title compound (Example 77, 5.0 mg, 15% yield) as a solid. 1H NMR (400 MHz, methanol-d4) δ 8.09 (d, J=2.27 Hz, 1H), 7.56 (dd, J=8.59, 2.53 Hz, 1H), 7.09 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 6.10 (s, 1H), 4.77 (s, 2H), 4.60-4.70 (m, 1H), 3.55-3.63 (m, 4H), 3.35 (t, J=6.06 Hz, 2H), 2.92-3.02 (m, 4H), 2.75 (t, J=6.06 Hz, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 1.36 (d, J=5.81 Hz, 6H); MS 536.3 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][C@H:8]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17](=[O:43])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[C:28]([C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[OH:42])=[N:29][N:30]([CH2:32][CH2:33][OH:34])[CH:31]=2)=[CH:21][CH:20]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC(O)=C(C2C(C#CC3C=CC(NC([C@@H]4COCCN4)=O)=CC=3)=CN(CCO)N=2)C=1.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:50])[NH:7][C@H:8]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[C:17](=[O:43])[NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:27]2[C:28]([C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[OH:42])=[N:29][N:30]([CH2:32][CH2:33][OH:34])[CH:31]=2)=[CH:23][CH:24]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCOCC1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCOC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1

Procedure:
Using the same procedure for the preparation of 18A, reaction of compound 21A with BOC-D-Phg-OH (11A) afforded the title compound 22A as a white powder in similar yield. 1H NMR (CDCl3, 500 MHz) δ 10.60 (s, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 7.90 (d, 2H, J=8.5 Hz), 7.78 (s, 1H), 7.56 (d, 2H, J=8.5 Hz), 7.43 (m, 5H), 7.20 (dd, 1H, J=8.5, 1.5 Hz), 6.97 (d, 1H, J=9.0 Hz), 5.48 (d, 1H, J=6.5 Hz), 5.40 (d, 1H, J=6.0 Hz), 5.29 (s, 1H), 4.81 (d, 1H, J=12.0 Hz), 4.31 (t, 2H, J=5.0 Hz), 4.06 (m, 2H), 3.78 (d, 1H, J=10.5 Hz), 3.64 (t, 1H, J=12.5 Hz), 3.59 (t, 1H, J=1.0 Hz), 3.43 (dd, 1H, J=11.0, 2.5 Hz), 3.06 (t, 1H, J=10.5 Hz), 1.93 (t, 1H, J=5.0 Hz), 1.45 (s, 9H). LCMS (ESI) m/z 722.16 (MNa+), 700.18 (MH+), 644.13 (100), 600.11, 354.11. HPLC: tR=4.48 min.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C(OCC)(=O)C>[CH2:1]([NH:3][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([O:7][C:6]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:5]=2[Cl:4])[CH:9]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(Cl)c1cccc(Oc2cc(Cl)ccc2Cl)c1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1cccc(Oc2cc(Cl)ccc2Cl)c1
Yield: 90.7 %

Procedure:
Ethyl acetate (50 ml) was added to 1.4 g of an aqueous ethylamine solution (70 %), and an ethyl acetate solution containing 3.0 g of 3-(2,5-dichlorophenoxy)benzoic acid chloride was dropwise added thereto with stirring, during which the reaction mixture was cooled in an ice bath. After the addition was finished, the mixture was stirred for 1 hour at room temperature. The reaction mixture was washed with 1 N hydrochloric acid, water, 1% aqueous sodium hydroxide solution and water saturated with sodium chloride in this order and dried over anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation to obtain 3.1 g of crude crystals. On recrystallizing the crude crystals from a benzene-hexane mixed solvent, 2.8 g of N-ethyl-3-(2,5-dichlorophenoxy)benzamide were obtained. Melting point, 74.5°-75.5° C. Elementary analysis: Calcd. for C15H13Cl2NO2 : C, 58.08%; H, 4.22%; N, 4.52%; Cl, 22.86%. Found: C, 58.16%; H, 4.25%; N, 4.49%; Cl, 22.97%. NMR: δCCl 4: 1.15 (t 3H), 3.34 (quintet 2H), 6.65-7.61 (8H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncn2)C1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 7.4 %

Procedure:
1-(8-Chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyrimidin-4-yl-propan-2-ol (200 mg, 0.56 mmol) was dissolved in DCM (5 mL), and a drop of DMF was added. The solution was cooled to 0° C. and a solution of thionyl chloride (0.2 mL) in 1 mL DCM was added dropwise. The solution was stirred at RT for 30 min. and at RT for 2.5 h. Volatiles were evaporated under reduced pressure, the residue was basified with ice cold aqueous 1N NaOH (10 mL) and the product was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to obtain 14 mg of product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.18 (s, 1H), 8.80 (d, 1H), 8.0 (s, 1H), 7.80 (d, 1H), 7.58 (s, 1H), 7.25 (m, 2H), 4.75 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:18])=[N:4][N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(NS(C1C=NC=C(C2C3C(=C(C4C=CC=CC=4)C=CC=3)C(Cl)=NN=2)C=1)(=O)=O)(C)(C)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].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[Cl:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2c(-c3ccccc3)cccc12
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Product: Nc1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Yield: 66.2 %

Procedure:
5-(4-Chloro-5-phenylphthalazin-1-yl)pyridin-3-amine (0.800 g, 66.1% yield) was prepared from 1,4-dichloro-5-phenylphthalazine (1.00 g, 3.63 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (0.960 g, 4.36 mmol, commercial), K3PO4 (0.772 g, 3.63 mmol), Pd2(dba)3 (0.0330 g, 0.0360 mmol) and tricyclohexylphosphine (0.0200 g, 0.0730 mmol) by the methods described for the preparation of N-(tert-butyl)-5-(4-chloro-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide in Example 1. The crude residue was taken to the next step without further purification. LCMS (Condition 11): retention time 0.86 min, [M+1]=333.1.
Reaction SMILES: F[C:2]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][N:7]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:20].CO[C:23]([C:25]1C=C2C(=CC=1N)CCC2)=O>>[CH:17]([O:16][C:14]([N:7]1[C:6]2[C:12](=[CH:2][C:3]3[CH2:20][CH2:23][CH2:25][C:4]=3[CH:5]=2)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:15])([CH3:19])[CH3:18]
Reactant: Cc1ccc2c(c1F)C(=O)CCCN2C(=O)OC(C)C
Reactant: COC(=O)c1cc2c(cc1N)CCC2
Product: CC(C)OC(=O)N1CCCC(=O)c2cc3c(cc21)CCC3

Procedure:
The titled compound was prepared following the procedure described for the preparation of isopropyl 6-fluoro-7-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (example 132, from step 3 to 5) by replacing methyl 2-amino-6-fluoro-5-methylbenzoate with 6-Amino-indan-5-carboxylic acid methyl ester in example 132 step 3. MS (ES+): 288 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>>[Cl:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(Cl)s1)C1CCNCC1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)s3)CC2)CC1

Procedure:
From (5-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (10 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (7 mg, intermediate AG) by procedure A.1. Yield: 9 mg (59%). White solid. MS (m/z): 397.4 ([M+H]+).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:22]N1C(=O)CCC1=O>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:15]([I:22])=[C:11]3[N:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(-c2cc3ncnc(NC4CCCC4)n3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Ic1c(-c2ccccc2)nn2c(NC3CCCC3)ncnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
N-Cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4amine (0.25 g, 0.90 mmol) was dissolved in dichlorornethane. To this solution was added N-iodosuccinimide (300 mg, 1.33 mmol) and the resulting solution was stirred at room temperature for 30 minutes. Additional dichloromethane was added and the reaction mixture was extracted with 1N aqueous sodium hydroxide and with water. The organic phase was dried (magnesium sulfate), filtered and concentrated to give a solid. This solid was purified by silica gel chromatography (ethyl acetate:hexane 1:1) to give 310 mg (85%) of N-cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a yellow solid. 1H-NMR (CDCl3): δ 8.35 (s, 1H), 7.98 (m, 2H), 7.55 (m, 3H), 6.64 (d, 1H), 4.60 (m, 1H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H); MS m/z 406 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]/[CH2:15]Cl)[C:6]=2[N:7]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CC#N>[NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12]/[CH:13]=[CH:14]/[CH2:15][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2C/C=C/CCl)c(=O)[nH]1
Reactant: CCOP(OCC)OCC
Solvent: CC#N
Product: CCOP(=O)(C/C=C/Cn1c(=O)sc2c(=O)[nH]c(N)nc21)OCC

Procedure:
A mixture of 5-Amino-3-[(E)-4-chloro-2-buten-1-yl]thiazolo[4,5-d]pyrimidine-2,7(3H, 6H)-dione (0.75 g, 2.75 mmol), anhydrous CH3CN (75 mL) and triethyl phosphite (10 mL) was stirred and heated at reflux for 6 days while adding additional quantities of triethyl phosphite (2×5 mL) at 2 day intervals. The mixture was evaporated and the residue was dissolved in CH2Cl2 (50 mL). The solution was applied to a silica gel column (5.5×20 cm) and the column was flash eluted with progressively increasing concentrations of MeOH in CH2Cl2 (%MeOH, vol in L): (0, 1), (1, 1), (2, 1), (3, 3), (5, 2), (10, 1). The eluate containing the product was evaporated and the solid residue was dried in vacuum for 16 h. The light yellow solid was stirred with 2-PrOH (10 mL) to obtain a white solid. The solid was collected and dried in vacuum at 85° C. for 3 days; 0.38 g (1.02 mmol, 37%), mp 191-192° C. Ir (KBr): ν3420, 3300 and 3190 (NH, NH2), 1690 (C=O), and 1666 broad (C=O, C=N, C=C) cm1. Uv, λmax (nm) (ε×10-3): pH 1, 302 (9.6), 250 (8.71), 220 (29.5); MeOH, 302 (9.00), 250 (8.55), 220 (29.0); pH 11, 292 (7.61), 248 (7.77), 224 (10.1). 1H nmr (DMSO-d6): δ1.17 (t, 6H, 2 CH3), 2.63 (dd, 2H, PCH2), 3.93 (q, 4H, OCH2), 4.34 (br s, 2H, NCH2), 5.43-5.49 (m, 1H, CH), 5.67-5.73 (m, 1H, CH), 6.95 (br s, 2H, NH2), and 11.14 (br s, 1H, NH). Anal. Calc'd for C13H19N4O5PS (374.35): C, 41.71; H, 5.11; N, 14.97; P, 8.27. Found: C, 41.68; H, 4.93; N, 15.01; P, 8.11.
Reaction SMILES: Cl[C:2]1(Cl)[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11].O>C(O)(=O)C.[Zn]>[CH2:2]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11]
Reactant: O=C1CC2(CCCCC2)C1(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2(CCCCC2)C1
Reaction time: 15 h

Procedure:
According to a literature procedure (Tetrahedron 1993, 49(36), 8159). A mixture of 1,1-dichlorospiro[3.5]nonan-2-one (5.00 g; 24.1 mmol) and zinc dust (4.74 g; 72.4 mmol) was stirred in acetic acid (60 mL) and water (30 mL) for 4 hours. The solution was then stored at −20° C. for 15 hours. The mixture was filtered through Celite®, washing with ether and hexane, and then the filtrate was washed with aqueous sodium hydroxide solution (2N; 4×100 mL). (This resulted in the precipitation of white salts, which needed to be removed by filtration). The organic phase was washed with water (30 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with hexane/ether (10:1) to give the desired product as an almost colorless oil (2.56 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[S:17][C:16]4[C:18]([N+:22]([O-])=O)=[CH:19][CH:20]=[CH:21][C:15]=4[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Ni]>[NH2:22][C:18]1[C:16]2[S:17][C:10]3[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)=[N:14][CH:13]=[N:12][C:11]=3[C:15]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc2c1sc1c(Nc3cccc(Br)c3)ncnc12
Agent: [Ni]
Solvent: CO
Product: Nc1cccc2c1sc1c(Nc3cccc(Br)c3)ncnc12
Yield: 47.1 %

Procedure:
A solution of 4-([3-bromophenyl]amino)-6-nitrobenzothieno[3,2-d]pyrimidine (160 mg, 0.4 mmol) in methanol (10 mL) was subjected to hydrogenation with Raney Nickel (0.07 g) at 25° C. for 30 hours. After the reaction was done, the solvent was removed under reduced pressure to leave a dark brown solid. Recrystalization from wet methanol afforded 6-amino-4-([3-bromophenyl]amino)benzothieno[3,2-d]pyrimidine as a brown solid (70 mg, 43%), mp 217.6-218.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([OH:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:21][C:22]1[C:27]([CH2:28][CH2:29]O)=[CH:26][CH:25]=[C:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:23]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:7])([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([O:19][CH2:29][CH2:28][C:27]2[C:22]([CH3:21])=[N:23][C:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)=[CH:25][CH:26]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)cc2ccccc12
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc2ccccc12

Procedure:
A] In analogy to the procedures described in example 4D] and 4E], 2-(3-hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester (example 14C]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (example 4K]) to give 2-methyl-2-(3-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-1-yloxy)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[CH3:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[CH2:20][Br:21])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccccc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccccc2)c1CBr
Yield: 82.4 %

Procedure:
A mixture of 1-benzyl-5-bromo-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (0.28 g, 0.83 mmol), N-bromosuccinimide (0.163 g, 0.92 mmol), and benzoyl peroxide (20 mg, 0.083 mmol) in CCl4 (10 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-20% EtOAc/hexanes) to give 284 mg of the title compound as an amorphous solid. MS: (+) m/z 415.87 (M+1).
Reaction SMILES: [Na].[C:2]1([CH3:22])[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28]>C(O)C>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([NH:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:22])=[CH:3][CH:4]=1)=[O:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Reactant: ClCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCl)(NC(=O)c1ccc(C)cc1)C(=O)OCC
Yield: 54.6 %

Procedure:
Sodium (6.42 g) was dissolved in 390 ml of ethanol at room temperature. To the solution was added 78.0 g of diethyl p-toluoylaminomalonate, and 47.9 g of 1-bromo-4-chlorobutane was added dropwise under heating to reflux. The mixture was heated to reflux for 20 hours. The reaction solution was concentrated. To the residue was added water, and the mixture was washed with ethyl acetate. After washing with 10% hydrochloric acid and water sequentially, the solution was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 55.7 g of the objective compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]C(C)(C)C.[CH3:16][S:17]SC>C1COCC1>[CH3:16][S:17][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cc[nH]c12
Reactant: CSSC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CSc1cccc2cc[nH]c12
Temperature: 0 °C
Yield: 56.1 %

Procedure:
To a solution of 7-bromo-1H-indole (3.0 g, 15.3 mmol) in THF (60 mL) at −78° C. was added tBuLi (1.7 M, 33.8 at, 57.4 mmol) and the mixture was allowed to warm to 0° C. The reaction was re-cooled to −78° C. and a solution of dimethyl disulfide (2.0 mL, 22.9 mmol) was added and the reaction was allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with ethyl acetate in hexanes (0-2%) to afford pure 7-(methylthio)-1H-indole (1.4 g, 55%). 1H NMR (400 MHz, CDCl3) δ=2.50 (s, 3H), 6.58 (dd, J=3.03, 2.02 Hz, 1H), 7.09 (t, J=7.58 Hz, 1H), 7.18-7.31 (m, 2H), 7.56 (d, J=7.83 Hz, 1H), 8.45 (br. s., 1H); MS (ES+): m/z 164.15 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Ethyl 1-(4-fluorophenyl)-3-methylpyrazole-5-carboxylate (2 g) was dissolved in a mixed solvent of ethanol (10 ml) and water (10 ml) and sodium hydroxide (0.4 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (1.4 g), melting point: 188° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]1([CH:13]=[C:14]2[C:19](=[O:20])[C:18](=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][O:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(Cl)Cl>CC(C)=O>[S:3]1[CH2:4][CH2:5][N:6]=[C:2]1[NH:1][C:19]1([OH:20])[C:18](=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][O:16][CH2:15][C:14]1=[CH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1=NCCS1
Reactant: O=C1C(=Cc2ccccc2)COCC1=Cc1ccccc1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: OC1(NC2=NCCS2)C(=Cc2ccccc2)COCC1=Cc1ccccc1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A solution of 2-amino-2-thiazoline (2.2 g, 22 mmole) in 100 ml of acetone is added to a suspension of tetrahydro-3,5-bis(phenylmethylene)-4H-pyran-4-one (5.0 g, 18 mmole) in 50 ml of acetone and heated at reflux temperature for 5 hours and then kept at room temperature overnight. Chloroform (75 ml) is added to the stirred mixture and, after 10 minutes, the product is collected and washed with acetone to give 3.1 g of crude product. When the filtrate, concentrated and resuspended in acetone, is stirred with additional 2-amino-2-thiazoline (2.2 g) at room temperature overnight, another 2.5 g is isolated for a combined yield of 5.6 g (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[N:3]=1.O1CCCC1.C[Si](C)(C)[C:18]([F:21])([F:20])[F:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([CH:6]([OH:7])[C:18]([F:21])([F:20])[F:19])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1nc(Cl)ccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)ccc1C(O)C(F)(F)F
Temperature: 0 °C

Procedure:
6-Chloro-2-methylnicotinaldehyde (250 mg, 1.6 mmol) was added to tetrahydrofuran (10.7 ml) and cooled to 0° C. Trimethyl(trifluoromethyl)silane (0.3 ml, 1.9 mmol) was added followed by tetrabutylammonium fluoride (1.9 ml, 1.0M in THF, 1.9 mmol). The reaction mixture was allowed to warm to room temperature over 1 hour. The reaction was then diluted with water and brine and extracted with ethyl acetate (3×). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the title compound as a solid.