Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]O.[Bi](Br)(Br)Br.[OH:7][CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)[CH3:9]>ClC(Cl)(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([CH:8]([O:7][CH3:1])[CH3:9])=[CH:11][CH:12]=1
Reactant: CO
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To the solution of methanol (53 mg, 1.67 mmol) in perchloromethane (80 mL) was added bismuth (III) bromide (743 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, the methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl-4-(1-methoxyethyl)benzoate (185 mg, 57%), as oil.
Reaction SMILES: [CH3:1]I.[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13][C:14]2[C:15](=[O:21])[NH:16][C:17](=[S:20])[NH:18][CH:19]=2)[CH:4]=1.[OH-].[K+]>C(O)C>[CH3:1][S:20][C:17]1[NH:16][C:15](=[O:21])[C:14]([CH2:13][C:5]2[CH:4]=[N:3][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:19][N:18]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cnc2ccccc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(Cc2cnc3ccccc3c2)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
Methyl iodide (0.56 g) was added to a stirred solution of 1,2-dihydro-5-[(3-quinolinyl)methyl]-2-thioxo-4(3H)-pyrimidinone (1.2 g) and potassium hydroxide (0.23 g) in aqueous ethanol (50%, 20 ml) at 60°. After 30 min., the solution was cooled and the solid which separated was crystallised from aqueous ethanol to give the title compound (1.1 g), m.p. 220°-221°.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1.O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([S:28]([N:31]=[CH:32][N:33]([CH3:34])[CH3:35])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH:7]=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(SC)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc(SC)cn1Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 g de 2-butyl 4-(methylthio) 1H-imidazole is dissolved in 120 cm3 of THF. Then 1.55 g of sodium hydride at 50% dispersion in oil is added slowly to the orange-coloured solution obtained. The temperature increases to 25° C. Agitation is carried out for 30 minutes at this temperature then 14 g of 4'-bromomethyl N-[(dimethylamino) methylene](1,1'-biphenyl) 2-sulphonamide is introduced. Agitation is carried out at ambient temperature until evolution ends, i.e. for approximately 3 hours, followed by taking up in water, extracting with ethyl acetate, separating by chromatography on silica eluting with ethyl acetate then impasting in iso ether, filtering and drying. In this way 9.35 g of expected product (colourless crystals) is obtained.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:13][CH2:12][N:11]3[C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:23]([S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH:22]=4)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]3[CH2:9]2)[CH2:3][CH2:2]1.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[C:60]([CH:65]=O)=[CH:61][CH:62]=[CH:63][CH:64]=2)=[CH:55][CH:54]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH2:65][N:1]2[CH2:7][CH2:6][CH2:5][CH:4]([N:8]3[CH2:13][CH2:12][N:11]4[C:14]([NH:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH2:29][CH2:30][N:31]6[CH2:32][CH2:33][O:34][CH2:35][CH2:36]6)=[C:23]([S:45]([C:48]([F:49])([F:50])[F:51])(=[O:47])=[O:46])[CH:22]=5)(=[O:19])=[O:20])=[N:15][N:16]=[C:10]4[CH2:9]3)[CH2:3][CH2:2]2)=[CH:57][CH:58]=1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Nc1nnc2n1CCN(C1CCCNCC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=S(=O)(Nc1nnc2n1CCN(C1CCCN(Cc3ccccc3-c3ccc(Cl)cc3)CC1)C2)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
To a vial containing N-(7-azepan-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide (62 mg, 0.080 mmol) and 4′-chloro-biphenyl-2-carbaldehyde (52.1 mg, 0.241 mmol) was added methanol (2.5 mL) under nitrogen. The reaction was stirred in an ice bath for 10 minutes and then acetic acid (5.51 μL, 0.096 mmol) was added. After stirring in the ice bath for an additional 15 minutes, sodium cyanoborohydride (40.3 mg, 0.642 mmol) was added. The reaction was then allowed to warm to ambient temperature and stir for 72 hours. The reaction mixture was concentrated, filtered and purified via flash chromatography on silica gel (10-50% methanol in CH2Cl2) to afford the title compound (50 mg, 64% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:32][CH:33]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:34])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC[C@@H](O)CO)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC[C@@H](O)CO)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N—((R)-2,3-dihydroxypropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=502.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[Br:19]Br>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:19][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]=1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: N#Cc1ccc(Cc2cc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Cc2oc3ccccc3c2Br)cc1
Temperature: 2 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.2 g (5 mmol) of 4-(benzofuran-2-yl)methyl-benzonitrile in 25 ml methylene chloride, a solution of 0.8 g (5 mmol) of bromine in 5 ml carbon tetrachloride is added dropwise at 2° C. The solution is stirred for 90 minutes at 2° C., the precipitate formed is suction filtered, washed with a little methylene chloride and dried.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:11]2)(=[O:4])[CH3:3].[CH2:20](I)[CH2:21][CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:16]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19])[CH2:11]2)(=[O:4])[CH3:3]
Reactant: CCCNC1CCc2c(cccc2NC(C)=O)C1
Reactant: CCCCI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reaction time: 8 h

Procedure:
2.83 g (0.010 mol) of 5-acetylamino-2-n-propylamino-tetraline-hydrochloride (Example 4.1.1), 2.76 g (0.015 mol) of n-butyliodide and 1.68 g (0.020 mol) of sodium hydrogen carbonate are refluxed in a mixture of 20 ml of absolute dimethylformamide and 30 ml of absolute tetrahydrofuran for 48 hours with stirring (moment of complete reaction determined by thin layer chromatography). The reaction mixture is concentrated by rotary evaporation, finally at 95° C. under a complete water-jet vacuum. The residue is shaken with 50 ml of methylene chloride and 50 ml of water and the aqueous phase separated is extracted twice more with 15 ml of methylene chloride. The combined extracts are washed with 20 ml of water, dried with sodium sulphate and concentrated by rotary evaporation, finally at 90° C. under a complete water-jet vacuum. The residue is dissolved with 10 ml of ethanol and the solution is acidified with 4.0 ml of 2.5 N ethanolic hydrochloric acid (0.0I mol HCl). After the addition of diethylether until turbidity is just starting, the title compound crystallises. After standing overnight it is suction filtered at 5° C., washed with a mixture of ethanol and ether and dried at 80° C. until a constant weight is obtained. Yield 2.56 g (75.5% of theory), melting point 217° C. After recrystallisation from methanol/ether the melting point does not change.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:16]1([CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Reaction time: 12 h
Yield: 62.4 %

Procedure:
Tert-butyl piperazine-1-carboxylate 7a (6.14 g, 33 mmol), bromomethyl-cyclopropane (4.05 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) were dissolved in 70 mL of dichloromethane. The reaction solution was stirred for 12 hours. The resulting solution was added with 50 mL of aqeuous saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (4.50 g, yield: 62.5%) as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C(OCC)(=O)C>[CH2:12]([NH:16][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCCCN
Solvent: CCOC(C)=O
Product: CCCCNC(=O)CCc1ccccc1

Procedure:
Following the procedure of Example 1 above and using 3-phenylpropionyl chloride and n-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a white solid, m.p. 26.7-33.1° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[N:10]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:18](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(NCC(=O)N(C)C)c(N)c1
Solvent: CC#N
Product: Cc1cc(C)c2c(c1)[nH]c(=O)n2CC(=O)N(C)C
Reaction time: 1 h

Procedure:
To a solution of N2-(2-amino-4,6-dimethylphenyl)-N1,N1-dimethylglycinamide from Step B (930 mg, 4.20 mmol) in CH3CN (20 mL) at 0° C. was added triphosgene (1.25 g, 4.20 mmol). The reaction mixture was stirred for 1 h, then quenched with H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Product: COc1ccc(CN2CCc3c(-c4ccc(Cl)cc4)nn(Cc4ccccc4)c3CC2)cc1OC

Procedure:
The title compound was prepared (12 mg) from 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C29H30ClN3O2, 487.20; found, m/z 488.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.43 (m, 2H), 7.30-7.29 (m, 2H), 7.25-7.22 (m, 2H), 7.20-7.18 (m, 1H), 7.03-7.02 (m, 2H), 6.86 (d, J=1.7 Hz, 1H), 6.76-6.71 (m, 2H), 5.25 (s, 2H), 3.79 (s, 6H), 3.63 (s, 2H), 2.72 (s, 4H), 2.68-2.66 (m, 4H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:36])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][OH:30])[CH2:27][CH2:26][C:25]5=[O:31])=[CH:20][C:19]=4[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)(O[CH3:41])(=O)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:36])[C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[C@H:28]([CH2:29][O:30][CH3:41])[CH2:27][CH2:26][C:25]5=[O:31])=[CH:20][C:19]=4[S:32]([CH3:35])(=[O:33])=[O:34])=[O:17])[CH2:14][CH2:15]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CC[C@H]3CO)cc2S(C)(=O)=O)CC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COC[C@@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)c(S(C)(=O)=O)c1

Procedure:
Using (S)-1-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (240 mg) described in Example 298 and methyl tosylate (71 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (28 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH:15]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]4[C:7]5=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]5[CH:12]=[CH:11][C:10]4=[O:13])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A suspension of [3-(methyloxy)-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl]acetaldehyde (185 mg 0.84 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h) (283 mg, 0.84 mmol) in chloroform (10 mL) and methanol (1.5 mL) was stirred at room temperature under argon for 1 h before addition of sodium triacetoxyborohydride (515 mg, 2.52 mmol). The reaction was stirred at rt overnight. A saturated solution of sodium bicarbonate (20 mL) was added to the reaction and the aqueous phase was extracted with 10% MeOH/DCM (3×50 mL).The combined organic phases were dried (MgSO4), filtered and evaporated and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford 252 mg of the title compound (60%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH2:9][C:8]2=[O:16])=O.[NH3:17].O>>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:7]([C:8](=[O:16])[CH2:9][CH2:10]2)=[CH:6][C:5]=1[C:3]([NH2:17])=[O:2]
Reactant: N
Reactant: COC(=O)c1cc2c(cc1OC)CCC2=O
Solvent: O
Product: COc1cc2c(cc1C(N)=O)C(=O)CC2
Temperature: 40 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
6-Methoxy-3-oxo-indan-5-carboxylic acid methyl ester (7 g, 31.82 mmol) was suspended in NH3.H2O (150 ml), and the mixture was heated to 40° C. and stirred for two hours, during this time the precipitate was formed. The precipitate was collected and dried to give product as white solid (5.2 g, 80% yield). LC-MS: m/e 206(MH+)
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([CH3:47])[C:41]=1[CH3:48].C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([CH3:48])[C:42]=1[CH3:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 74%).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24](I)[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(N(CC)CC)C.CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(I)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Reaction time: 8 h

Procedure:
A solution of the product of Stage b), (0.8 g, 1.69 mmoles), bis(triphenylphosphine) palladium (II) chloride (25 mg) and copper (I) iodide (25 mg) in dry triethylamine (40 ml) and N,N-dimethylformamide (3 ml) was degassed thoroughly with nitrogen. (Trimethylsilyl) acetylene (0.47 ml, 3.37 mmoles) was added and the mixture stirred under N2 at 50° for 8 hours. The solvent was removed under reduced pressure, the residue dissolved in methylene chloride (40 ml) and the solution washed with 2% aqueous disodium EDTA solution (4 ml), water (50 ml) and dried (sodium sulphate). Evaporation of the solvent and purification of the residue by silica column chromatography eluting with 2% MeOH/CH2Cl2 afforded the title compound. Trituration with ether/hexane afforded analytically pure title compound as an off-white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Yield: 65.8 %

Procedure:
A mixture of 0.030 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.017 g (0.0001 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.028 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-1) as an off-white solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:8][C:6]1[CH:7]=[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Sc1ccccc1
Reactant: CC(=O)c1c(C)cc(I)cc1C
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Sc2ccccc2)cc1C
Yield: 65.5 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), benzenethiol (0.60 mL, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6-dimethyl-4-(phenylthio)phenyl)ethanone (931 mg, 3.6 mmol) as yellow oil in 66% yield: 1H NMR (CD3OD, 500 MHz) δ 7.34-7.35 (m, 5 H); 6.97 (s, 2 H), 2.46 (s, 3 H), 2.17 (s, 6 H); ESI-MS: m/z 257.0 (M+H)+.