Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1.[Li+].CC([N-]C(C)C)C.CN([CH:26]=[O:27])C>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH:26]=[O:27])[N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: CN(C)C=O
Reactant: Ic1cn(CCc2ccccc2)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc(I)cn1CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 4-iodo-1-phenethyl-imidazole (example 2C) (563 mg, 1.89 mmoles) in THF (13 mL) under argon is cooled to −78° C. A 2.0M LDA solution (1.04 mL, 2.08 mmoles) is added dropwise. After 30 minutes at −78° C., DMF (161 μL, 2.08 mmoles) is added dropwise. The reaction mixture is allowed to reach 0° C., then it is quenched by adding a half-saturated NaHCO3 solution. The aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (heptane:AcOEt) as eluent with a gradient from (95:5) to (70:30) to give 4-iodo-1-phenethyl-imidazole-2-carbaldehyde.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([S:9][C:10]1[NH:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][N:11]=1)[C:5]([O:7]C)=[O:6].CO.O1CCCC1.[Li]>O.Cl>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([S:9][C:10]1[NH:14][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:12][N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(CC(C)C)Sc1nnc(-c2ccccc2)[nH]1
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(Sc1nnc(-c2ccccc2)[nH]1)C(=O)O

Procedure:
Methyl 4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanoate (473 mg, 1.54 mmoles) in a mixture of water (2 mL), methanol (2 mL) and tetrahydrofuran (4 mL) was treated with lithium hydroxyde monohydrate (193 mg, 4.6 mmoles) until disappearance of the starting material was observed by TLC. The reaction was diluted with 1.2 N hydrochloric acid until pH 1. The aqueous phase was extracted 3 times with dichloromethane. The organic phase was concentrated under reduced pressure to yield a crude residue of 4-methyl-2-[(5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]pentanoic acid which was used as such in the next reaction.
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[F:57][C:58]([F:67])([F:66])[C:59]1[CH:64]=[CH:63][N:62]=[CH:61][C:60]=1[NH2:65].CC([O-])(C)C.[Na+]>>[CH3:54][N:44]1[C:45]2[C:50](=[CH:49][C:48]([NH:65][C:60]3[CH:61]=[N:62][CH:63]=[CH:64][C:59]=3[C:58]([F:67])([F:57])[F:66])=[CH:47][C:46]=2[C:52]#[N:53])[C@@H:42]2[CH2:41][NH:40][CH2:56][CH2:55][C@H:43]12
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: Nc1cnccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3cnccc3C(F)(F)F)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as a yellow solid (50 mg, 26%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 4-trifluoromethyl-pyridin-3-ylamine (141 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 374 (base, M+H).
Reaction SMILES: Br[CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4].[C:23]([O-:26])(=[O:25])[CH3:24].[K+]>C(O)(=O)C>[C:23]([O:26][CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4])(=[O:25])[CH3:24]
Reactant: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(OC(C)=O)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (323 mg) in acetic acid (3 ml) was added potassium acetate (345 mg) and the mixture was stirred at 60° C. for 2 hours. The resulting mixture was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-acetoxypropyl)-3-isobutyrylindole-6-carboxylate (207 mg).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.CI>O1CCCC1>[CH3:1][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: [Li]CCCC
Reactant: COC(=O)C1CCOCC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCOCC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
At −78° C., 22.1 ml of n-butyllithium (35.4 mmol, 1.6M in hexane) were slowly added dropwise to a solution of 4.91 ml (35.0 mmol) of diisopropylamine in 45 ml of tetrahydrofuran, and the mixture was stirred at −78° C. for another 10 min and at 0° C. for another 25 min. Subsequently, at −78° C., a solution of 5.00 g (34.7 mmol) of methyl tetrahydro-2H-pyran-4-carboxylate in 45 ml of tetrahydrofuran was added, and the mixture was stirred at −78° C. for another 15 min and at 0° C. for another 30 min. At −78° C., 2.16 ml (34.7 mmol) of methyl iodide were added dropwise, and the reaction mixture was slowly warmed to −25° C. and then to room temperature overnight. The reaction was terminated by addition of 80 ml of 0.1N hydrochloric acid, and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulphate and filtered and the solvent was removed under reduced pressure. The resulting suspension was triturated with 20 ml of methyl tert-butyl ether, the precipitate was filtered off with suction and the mother liquor was concentrated under reduced pressure, giving the title compound. Yield: 5.88 g (purity 95%, quant.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:9]/[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:5][C:6]=1[CH3:7].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:5][C:6]=1[CH3:7]
Reactant: COC(C/N=C/c1cc(Br)c(C)s1)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(CNCc1cc(Br)c(C)s1)OC
Temperature: 25 °C

Procedure:
(E)-N-((4-bromo-5-methylthiophen-2-yl)methylene)-2,2-dimethoxyethanamine (15.00 g, 51.34 mmol) was taken up in EtOH (50 ml) and treated with sodium borohydride (1.942 g, 51.34 mmol) slowly (some fizzing observed). The reaction was stirred at reflux for 3 hours and at room temperature overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate and water. The layer were separated and the organic layer washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was dried with sodium sulfate and concentrated under reduced pressure to give N-((4-bromo-5-methylthiophen-2-yl)methyl)-2,2-dimethoxyethanamine as a brown oil. MS (M+1) 295.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C=O)C>[N:17]1([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1NCCc2ccc(O)cc21
Reactant: ClCCCN1CCCC1
Solvent: CN(C)C=O
Product: O=C1NCCc2ccc(OCCCN3CCCC3)cc21

Procedure:
7-(3-Pyrrolidin-1-yl-propoxy)-3,4-dihydro-2H-isoquinolin-1-one is prepared from 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.48 g, 2.94 mmol) in a manner substantially analogous to Procedure A except DMF is used in place of dioxane and 1-(3-Chloro-propyl)-pyrrolidine is used instead of N-(3-chloropropyl)piperidine. Following aqueous workup, the crude material is purified by flash chromatography (Biotage 40M SiO2, elute 90/10/1 CH2Cl2/MeOH/NH4OH) to give the title compound as an off-white solid (0.17 g, 21%). MS (ES+) 275.1
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH2:15])([CH3:14])[CH3:13])=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](Cl)=[O:27]>C(N(CC)CC)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:15][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:18])([CH3:14])[CH3:13])=[CH:16][CH:17]=1
Reactant: CC(C)(N)c1ccc(F)cc1
Reactant: Cc1ccccc1CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccccc1CC(=O)NC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
Into a 300 ml four-necked flask, there were charged benzene (200 ml), 4-fluoro-α,α-dimethylbenzylamine (7.7 g) and triethylamine (6.0 g), and o-methylphenylacetyl chloride (9.5 g) was dropwise added thereto at room temperature while stirring, followed by refluxing for 3 hours. After cooling, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 11.3 g of N-(4-fluoro-α,α-dimethylbenzyl)-o-methylphenylacetamide (Compound No. 11). M.P., 150°-151° C.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][CH2:16][C:15]3[N:14]=[C:13]([NH:18][C:19]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])=[O:20])[CH:12]=[C:11]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:31]=[C:9]2[C:10]=34)=CC=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:24]1([C@H:22]([NH:21][C:19]([NH:18][C:13]2[CH:12]=[C:11]3[NH:30][N:31]=[C:9]4[C:10]3=[C:15]([CH2:16][CH2:17][NH:8]4)[N:14]=2)=[O:20])[CH3:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2CCc3nc(NC(=O)N[C@H](C)c4ccccc4)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc3c2c(n1)CCN3)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-1-(3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea (22 mg, 0.032 mmol) was taken in TFA (0.1 mL) and stirred at room temperature for 30 minutes. To the reaction was added triethylsilane (21 uL, 0.128 mmol) stirred for 15 minutes at room temperature then heated to 80° C. for 30 minutes. The reaction mixture was concentrated, taken in DCM and washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (R)-1-(1-phenylethyl)-3-(1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea. MS ESI calc'd. for C17H18N6O [M+H]+ 323. found 323. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.45 (br, s, 1H), 7.38 (m, 4H), 7.20 (m, 1H), 7.00 (s, 1H), 6.23 (s, 1H), 4.83 (m, 1H), 3.42 (dd, J=8.0, 5.0 Hz, 2H), 2.80 (dd, J=8.0, 5.0 Hz, 2H), 1.40 (d, J=11 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][C:34](=[O:36])[CH3:35])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol)) in DCM (15 mL) was added pyridine (0.0200 mL, 0.253 mmol) followed by acetyl chloride (0.0140 mL, 0.202 mmol) and the reaction mixture stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-111 as described in general methods) to give N-(1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)acetamide (25.0 mg, 37.3%) as white solid. LCMS Condition B-34: retention time 2.14 min, [M+1]=399.0. HPLC Condition B-31: retention time 6.09 min, Purity 99.83%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.01 (m, 2H), 1.35-1.41 (m, 2H), 1.85 (s, 3H), 4.68 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 6.99 (t, J=4.9 Hz, 1H), 7.27 (dd, J=6.5 Hz, J=4.9 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.40-7.48 (m, 1H), 7.48-7.57 (m, 4H), 7.67 (d, J=2.7 Hz, 1H), 7.76 (td, J=7.7 Hz, J=1.7 Hz, 1H), 8.37-8.41 (m, 1H), 8.44 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([NH2:27])[CH:26]=1)=[O:21].[Br:28]N1C(=O)CCC1=O.O>O1CCCC1>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]([F:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:19][C:20]([C:22]1[S:23][C:24]([Br:28])=[C:25]([NH2:27])[CH:26]=1)=[O:21]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)c(Br)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of 4-amino-thiophene-2-carboxylic acid [2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-amide (360 mg, 0.87 mmol) (Example I3) in tetrahydrofuran (20 ml) was added N-bromosuccinimide (NBS) (155 mg, 0.87 mmol). The mixture was stirred at room temperature for 1.5 hours. Water (50 ml) was added and the organic phase was extracted twice with ethyl acetate (50 ml). The combined organic extracts were dried over sodium sulfate and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane) to give 5-bromo-4-amino-thiophene-2-carboxylic acid [2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-amide (343 mg; 80% yield); 1H-NMR (CDCl3, 400 MHz): 7.26 (s, 2H), 7.10 (s, 1H), 3.8 (s, 2H), 2.24 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1.[NH:52]([CH2:55][CH3:56])[CH2:53][CH3:54].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=1
Reactant: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3C=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CC)Cc1ccccc1CS(=O)(=O)NCCc1c(CCCc2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 41.3 %

Procedure:
As outlined in Example 17, Step 1 methyl 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (Example 16, Step 5, 58 mg, 0.081 mmol) was reacted with HNEt2 (0.022 mL, 0.21 mmol) and NaBH(OAc)3 (56 mg, 0.26 mmol) in DCE (2 mL) to afford methyl 4-{3-[5-chloro-2-{2-[({2-[(diethylamino)methyl]benzyl}sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate (26 mg, 41%) and the side product methyl 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(hydroxymethyl)benzyl]sulfonylamino}ethyl]-1H-indol-3-yl}propyl)benzoate (8.6 mg, 15%), both as white solids.
Reaction SMILES: CN1C([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH2:23][CH2:24][C:25]5[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=5)[N:27]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=CC=N1.OCC[N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[F:34][C:31]([F:32])([F:33])[C:28]1[N:26]2[N:27]=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:38]5[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]5)=[CH:11][CH:12]=4)[CH2:21][CH2:20]3)[CH:23]=[CH:24][C:25]2=[N:30][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: Cn1nccc1CCOc1ccc(N2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Yield: 60 %

Procedure:
Obtained in 60% yield by an analogous method to Example 29, preparation of starting materials, starting from 4-{4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}phenol (obtained as described in Example 16, preparation of starting materials) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (CAS 77279-24-4).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH:1]1([NH:7][C:8]2[S:9][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(NC2CCCCC2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 17 g of cyclohexylthiourea, 22 g of ethyl bromopyruvate and 200 ml of ethanol, giving the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH3:9][O:10][C:11]1[C:24]2[O:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([C:25](Cl)=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[C:24]=3[O:23][C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:26])=[N:6]1)[CH3:8]
Reactant: COc1cccc2c1Oc1ccccc1C2C(=O)Cl
Reactant: CCn1nnc(N)n1
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3c(OC)cccc32)n1

Procedure:
The title compound, white solid, m.p. 239-240° C. (dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and (RS)-4-methoxy-9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[F:10][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[F:10][C:5]1[S:1][C:2]([NH:6][C:7](=[O:9])[CH3:8])=[N:3][CH:4]=1
Reactant: F[B-](F)(F)F
Reactant: CC(=O)Nc1nccs1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(=O)Nc1ncc(F)s1
Temperature: 80 °C
Yield: 41.4 %

Procedure:
To a solution of N-(thiazol-2-yl)acetamide (150 g, 1056 mmol, Combi-Blocks, San Diego, Calif.) in acetonitrile (3 L) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) (486 g, 1373 mmol, Air Products, Allentown, Pa.) and the mixture was heated at 80° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and water (2 L) was added. The mixture was extracted with ethyl acetate (2×1.5 L). The combined organic extract was washed with saturated aqueous NaHCO3 (1.5 L) and 2N HCl (1 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude N-(5-fluorothiazol-2-yl)acetamide (70.0 g, crude) which was used for next reaction without any purification. m/z (ESI) 161.0 (M+H)+
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:15]=23)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ccnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(OC)cc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a4) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])[N:8]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].CN(C)C=O.C(OCC)(=O)C>O.C(Cl)Cl>[CH2:32]([N:34]([CH2:2][C:3]1[CH:31]=[CH:30][C:6]2[C:7](=[O:29])[N:8]([C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1)[CH2:35][CH3:36])[CH3:33]
Reactant: O=c1c2ccc(CBr)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNCC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCN(CC)Cc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
30.0 g of 6-(bromomethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one and 13.9 mL of diethylamine were added to 90 mL of N,N-dimethylformamide. This was stirred for 50 minutes at room temperature. Ethyl acetate, methylene chloride and water were added to the reaction mixture, and an organic layer was separated. Water and hydrochloric acid were added to the organic layer, and an aqueous layer was separated. An organic layer was extracted with water and, together with the aqueous layer, 180 mL of acetone was added and 13 mL of a 20% sodium hydroxide aqueous solution was added dropwise. Solids were filtered to obtain 22.2 g of 6-(diethylamino)methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one was obtained in the form of a pale yellowish-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)(C)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CC(C)O
Product: c1ccc(CN2CCc3c(ncnc3N3CCOCC3)C2)cc1
Yield: 100.1 %

Procedure:
To a solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 4a (0.46 g, 1.77 mmol) in isopropanol (20 mL) was added morpholine (0.38 g, 4.42 mmol), and the reaction mixture was heated to reflux for 18 h. The solvent was removed in vacuo, and the residue was suspended in a saturated solution of NaHCO3, and the product was extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to provide a residue, which was purified by chromatography to give 0.55 g of 7-benzyl-4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 5a as a pale yellow liquid.