Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([C:27](=[O:31])[C:28]([OH:30])=O)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[C:62]([NH2:67])=[CH:63][CH:64]=[CH:65][CH:66]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][C:28](=[O:30])[C:27]([N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C@H:10]1[CH2:11][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)=[O:31]
Reactant: COCCCCNc1ccccc1N
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCNc1ccccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo)acetic acid (10.3 g), HOBt (4.13 g) and WSC.HCl (6.28 g) were dissolved in DMF (50 ml), N-(4-methoxybutyl)benzene-1,2-diamine (4.67 g) and diisopropylethylamine (11.3 ml) were added, and the mixture was stirred at room temperature for 15 hr and at 60° C. for 2 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (9.11 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12].[CH3:21]I>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(F)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1ccc(F)cc1Br)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Add sodium hydride (0.89 g, 22.4 mmol, 60% dispersion in mineral oil) to a solution of tert-butyl 1-(2-bromo-4-fluorophenyl)ethylcarbamate (4.75 g, 14.9 mmol) in DMF (10 mL). Stir the mixture for 30 min at RT. Add methyl iodide (1.86 mL, 29.9 mmol). Stir the mixture for 1 h at RT. Dilute with ethyl acetate, and wash with water and aqueous saturated sodium chloride. Dry over sodium sulfate and concentrate. Purify by column chromatography (hexane to 20% ethyl acetate in hexane) to give the title compound as a colorless oil (4.9 g, 98%). 1H NMR (400 MHz, CD3Cl) δ 1.32 (s, 9H), 1.45 (t, J=8.0 Hz, 3H), 2.58 (s, 3H), 5.39 (br, 1H), 7.00 (m, 1H), 7.28 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[S:15][CH:16]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[S:15][CH:16]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: COC(=O)c1cc(N)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1

Procedure:
A solution of 4-bromo-pyridine-2-carboxylic acid (1.98 g, 9.80 mmol), methyl 4-aminothiophene-2-carboxylate (1.40 g, 8.91 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (4.07 g, 10.7 mmol), and N-methylmorpholine (1.18 mL, 10.7 mmol) in N,N-dimethylformamide (18 mL) was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, the residue suspended in acetonitrile, and the solids were isolated by filtration. The solids were washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL), and dried under reduced pressure to afford methyl 4-(4-bromopicolinamido)thiophene-2-carboxylate, a compound of formula (19) as a white powder (2.70 g, 90% yield). M+1=341.1.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])=[O:23])=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(C(C)(C)C)(C(C)(C)C)C(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(C)C=CC=CC=1>[NH:21]([C:22](=[O:23])[CH:24]([C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=1
Reactant: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
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: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a mixture of tert-butyl 4-bromobenzoate (7.349 g, 28.6 mmol), malondianilide (6.01 g, 23.7 mmol), and K3PO4 (15.15 g, 71 mmol) was added Pd2(dba)3 (996 mg, 1.09 mmol), toluene (50 mL), and P(tert-Bu)3 (1.08 mL, 4.35 mmol). The reaction mixture was degassed and heated to 70° C. for 16 h, additional Pd[P(tert-Bu)3]2 was added and the reaction was heated to 80° C. After 24 h, the reaction mixture was diluted with ethyl acetate, washed with water (1×), brine (1×), dried over MgSO4, and concentrated. tert-Butyl 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoate was used without further purification: ESIMS calcd 431.2 (M++H), found 431.1 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].Cl.[NH2:16][CH2:17][C:18]#[N:19]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12](=[O:14])[NH:19][CH2:18][C:17]#[N:16])=[O:5])[CH3:2]
Reactant: N#CCN
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)NCC#N

Procedure:
The reaction of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester and aminoacetonitrile hydrochloride performed in analogy to example 1, step 8 yielded the title compound as a pale brown solid. MS: 237.3 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: COc1cc(C(=O)O)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Yield: 86.7 %

Procedure:
In the same manner as in Example 259 and using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (80 mg, 0.52 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (160 mg, 85%) was obtained as a white solid. melting point 224° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH3:23])=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][CH2:2][C:3]2[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=2[O:13][CH3:14])[C:19]([CH3:23])=[CH:18][N:17]=1
Reactant: COc1ccc(S(C)(=O)=O)cc1CBr
Reactant: Cc1cnc(Cl)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(C)(=O)=O)cc1CNc1nc(Cl)ncc1C
Temperature: 100 °C

Procedure:
2-(Bromomethyl)-1-methoxy-4-(methylsulfonyl)benzene VI-1 (1 g, 3.6 mmol, prepared by Procedure H) was added to a stirred solution of 2-chloro-5-methylpyrimidin-4-amine (1 g, 6.9 mmol) and K2CO3 (1 g, 7.2 mmol) in acetonitrile (10 mL) and heated overnight at 100° C. The mixture was filtered, concentrated in vacuo and purified by flash chromatography (ethyl acetate/petrol) to afford 2-chloro-N-(2-methoxy-5-(methylsulfonyl)benzyl)-5-methylpyrimidin-4-amine as a yellow solid. LC-MS (Method C) RT=0.93 min (ES+) 342.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:28]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N:8]2[C:9](=[O:26])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH3:27])=[CH:35][CH:34]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)Oc1ccc(B(O)O)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 72.1 %

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 4-tert-butoxyphenylboronic acid (0.54 g), triethylamine (0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.54 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.51 g, 72%).
Reaction SMILES: II.C[Si](C)(C)[Si](C)(C)C.[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][CH2:21][CH:22]3[CH2:28][CH:27]4[N:29](NC(OCC)=O)[CH:24]([CH2:25][CH2:26]4)[CH2:23]3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1>ClC(Cl)C>[CH:27]12[NH:29][CH:24]([CH2:25][CH2:26]1)[CH2:23][CH:22]([CH2:21][NH:20][C:16]1[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=1)[NH:11][N:12]=[CH:13]3)[CH2:28]2
Reactant: CCOC(=O)NN1C2CCC1CC(CNc1ccc3[nH]ncc3c1)C2
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: II
Solvent: CC(Cl)Cl
Product: c1cc2[nH]ncc2cc1NCC1CC2CCC(C1)N2
Temperature: 70 °C
Yield: 85.3 %

Procedure:
Iodine (599 mg, 2.36 mmol) was added to hexamethyldisilane (864 mg, 5.90 mmol) and the resulting mixture was heated to 70° C. with stirring. When the reaction solution became substantially colorless after violent reaction, it was cooled to room temperature. A solution of the ethyl 3-[(1H-indazol-5-ylamino)methyl]-8-azabicyclo[3.2.1]octane-8-carbamate (386 mg, 1.18 mmol) obtained in Example 541 in dichloroethane (8 ml) was added thereto, and the resulting mixture was stirred at 50° C. for 5 hours. The reaction was terminated by adding methanol (4 ml) under ice-cooling, and then the solvent was distilled off under reduced pressure. Chloroform/aqueous ammonia was added to the residue, followed by extraction with chloroform, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby N-(8-azabicyclo[3.2.1]oct-3-ylmethyl)-1H-indazol-5-amine (258 mg, 85%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH:17]1[CH2:19][CH2:18]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH:17]1[CH2:18][CH2:19]1)[C:20]([F:22])([F:23])[F:21]
Reactant: COC(=O)C(O)(c1c(C2CC2)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccccc2)N=C1C1CC1)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 3-cyclopropyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (178 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (169 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Br[CH2:35][CH2:36][O:37][C:38](=[O:40])[CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:35][CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(=O)OCCBr
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)OCCN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (24 mg, 0.06 mmol, 1.0 equiv; Example 122) in anhydrous DMF (1 mL) was added lithium aluminum hydride (2.3 mg, 0.06 mmol, 1.0 equiv; [CAS RN 16853-85-3]) and the reaction mixture stirred at rt. After 30 min, acetic acid 2-bromo-ethyl ester (12.0 mg, 8 μL, 0.072 mmol, 1.2 equiv; [CAS RN 927-68-4]) was added and the reaction mixture heated by microwave irradiation to 180° C. for 60 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μM, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 8.9 mg (31%) of the title compound as a light yellow powder. MS (ISP): 486.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:30]([O:24][CH2:23][CH:2]([OH:1])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO)cc2n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2,3-Dihydroxypropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1)(1.66 g, 5.04 mmol), imidazole (0.686 g, 10.08 mmol) and DMAP (0.062 g, 0.504 mmol) were dissolved in DMF (25 ml) and TBS-Cl (0.836 g, 5.54 mmol) was added. The resulting mixture was stirred at RT overnight. Further TBS-Cl (0.836 g, 5.54 mmol) added and stirring continued for 2 hours. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3(aq) and brine (3×). The organic phase was dried over sodium sulphate and evaporated under vacuum. The residue was redissolved in DCM and evaporated onto silica. The silica was deposited onto a 25 g silica cartridge and the system eluted with 20% EtOAc/hexane, 40% EtOAc/hexane and 60% EtOAc/hexane. The product fractions were combined and evaporated to give tacky yellow solid. This solid was triturated with Et2O/hexane to afford the title compound;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13].[OH:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([NH:27][C:28](=[O:30])[CH3:29])=[CH:22][C:21]=1[CH3:31]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH:12]([C:11]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:9]([CH:10]=1)[CH2:8][O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([NH:27][C:28](=[O:30])[CH3:29])=[CH:22][C:21]=1[CH3:31])=[O:13]
Reactant: CC(=O)Nc1cc(C)c(O)c(C)c1
Reactant: COc1ccc(C=O)cc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(C=O)cc1COc1c(C)cc(NC(C)=O)cc1C
Temperature: 150 °C
Yield: 56 %

Procedure:
A suspension of 2,6-dimethyl-4-nitrophenol (4a, 1.58 g, 9.45 mmol) in AcOH (20 ml), MeOH (15 ml), and THF (10 ml) in a hydrogenator vessel was treated with acetic anhydride (6 ml, 63.6 mmol) and PtO2 (200 mg, 0.881 mmol), pressurized to 50 p.s.i. with H2 and shaken for 24 h. The reaction mixture was returned to atmospheric pressure, diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b) was isolated as a white solid that was pure based upon LCMS analysis and used without further purification. Potassium carbonate (810 mg, 5.34 mmol) was added to a solution of tetrabutylammonium iodide (78.9 mg, 0.534 mmol), 3-(chloromethyl)-4-methoxybenzaldehyde (5a, 197 mg, 1.07 mmol), and N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b, 211 mg, 1.18 mmol) in 20 ml of acetonitrile. The reaction mixture was heated to 150° C. in the microwave for 1 h, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with 5-50% EtOAc/DCM gradient to afford the desired product 6a (196 mg, 56%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.28 (s, 6 H), 3.93 (s, 3 H), 4.83 (s, 2 H), 7.02 (d, J=8.4 Hz, 1H), 7.13 (s, 1 H), 7.17 (s, 2 H), 7.89 (dd, J=8.4, 2.0 Hz, 1 H), 8.12 (d, J=1.8 Hz, 1H), 9.94 (s, 1 H); LCMS: (electrospray+ve), m/z 328.2 (MH)+, tR=3.16 min, UV254=>95%. N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (6a, 145 mg, 0.441 mmol), 2-amino-N-(furan-2-ylmethyl)benzamide (3b, 105 mg, 0.486 mmol), and 0.2 equiv of Yb(OTf)3 in 5 ml of EtOH were heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 7-60% ethyl acetate in hexanes to give the desired product 7a (40.9 mg, 0.078 mmol, 17.6% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.21 (s, 6 H), 3.77 (d, J=15.7 Hz, 1 H), 3.84 (s, 3 H), 4.41 (s, 1 H), 4.70-4.87 (m, 2 H), 5.35 (d, J=15.7 Hz, 1 H), 5.78 (s, 1 H), 6.20 (d, J=2.9 Hz, 1 H), 6.24-6.32 (m, 1 H), 6.53 (d, J=8.0 Hz, 1 H), 6.76-6.91 (m, 2 H), 7.03 (br. s., 1 H), 7.13 (s, 2 H), 7.30-7.37 (m, 2 H), 7.49 (d, J=2.0 Hz, 1 H), 7.92-8.03 (m, 1 H); LC/MS (electrospray+ve), m/z 526.2 (MH)+, Retention time t=5.71 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C31H31N3O5 [M+H]+526.2351, found 526.2350.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[NH:22]C(=O)OC(C)(C)C)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[NH2:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(NC(=O)OC(C)(C)C)cnn1-c1ncc(C)c(-c2cccs2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCc1c(N)cnn1-c1ncc(C)c(-c2cccs2)n1
Temperature: 23 °C
Reaction time: 23 h
Yield: 38 %

Procedure:
To the solution of tert-butyl 5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-ylcarbamate from step 1 in CHCl3 (30 mL) cooled to 0° C. was injected trifluoroacetic acid (3 mL) and let stir for 23 h at 23° C. The reaction solvent was then evaporated and redissolved in CH2Cl2 and washed with saturated NaHCO3 solution. The organic layer dried (sodium sulfate) and concentrated, whereupon the residue was purified by silica gel flash column chromatography (gradient from 2% methanol in dichloromethane to 10% methanol in dichloromethane) afford 5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-amine (361 mg, 38% yield over 3 steps) as a yellow oil. 1H NMR (500 MHz, DMSO) δ 8.55 (s, 1H), 7.83 (dd, J=3.91, 0.98 Hz, 1H), 7.69 (dd, J=5.38, 0.98 Hz, 1H), 7.46 (s, 1H), 7.21 (dd, J=4.89, 3.91 Hz, 1H), 4.86 (bs, 2H), 3.19 (t, J=7.82 Hz, 2H), 2.53 (s, 3H), 4.53 (m, 2H), 1.36 (sex, J=7.83 Hz, 2H), 0.84 (t, J=7.34 Hz, 3H). LCMS (ES+) m/z 314 (M+1).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:4]=1[NH:5]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C@H:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:4]1[NH:5]2
Reactant: c1ccc2c(c1)Cc1[nH]c3ccccc3c1-2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccc2c(c1)C[C@H]1Nc3ccccc3[C@@H]21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5,6-Dihydroindeno[2,1-b]indole (185 mg, 0.9 mmol) was reacted with sodium cyanoborohydride (310 mg, 5 mmol), in glacial acetic acid (5 cm3), for six hours. The solution was poured into ice/water, and stirred for one hour. It was then neutralised with sodium hydroxide, and the white solid which formed was collected by filtration, washed with water, dried and purified by "flash" chromatography (10% EtOAc/petrol 60°-80° C., Rf 30% EtOAc/petrol (60°-80° C.) 0.6) to yield the title compound as a colourless solid. Yield: (81 mg, (43%) M.p. 85°-86° C. 1H NMR (CDCl3) δ: 3.09 (1H, dd,), 3.33 (1H, dd,), 3.45 (1H, br,), 4.74 (1H, d,), 4.82 (1H, ddd,), 6.55 (1H, d,), 6.73 (1H, ddd,), 7.00 (1H, ddd,), 7.1- 7.4 (4H, m).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12].Cl[C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([C:9]1[S:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:6]([CH3:5])[CH:10]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Cl
Reactant: COC(=O)c1sccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1sc(C(C)(C)C)cc1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
AlCl3 (15.60 g, 117 mMol) was suspended in CH2Cl2 (18 mL) and the mixture was cooled to −78° C. A solution of 12.28 g (78 mMol) of 101a in CH2Cl2 (9 mL) was added dropwise over 5 min. The mixture was stirred for 5 min. A solution of 8.9 mL (82 mMol) 2-chloro-2-methylpropane in CH2Cl2 (9 mL) was then added over 45 min, and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was gradually warmed to room temperature and stirred for 24 h. The reaction mixture was then poured onto ice and extracted with CH2Cl2. The organic layer was dried with Na2SO4, and concentrated to an oil, which was purified on silica eluting with a gradient of CH2Cl2 in Hexane (0 to 10%) to afford 9.94 g (60%) of 101b.