Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([Cl:19])=[N:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:26]1[CH:30]=[C:29]([CH2:31][CH2:32][N:33]2C(=O)C3C(=CC=CC=3)C2=O)[N:28]=[C:27]1[C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CCO>[NH2:33][CH2:32][CH2:31][C:29]1[N:28]=[C:27]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:26]([CH:20]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17](=[O:18])[C:16]3[C:11]([N:10]=2)=[N:12][C:13]([Cl:19])=[N:14][CH:15]=3)[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:30]=1
Reactant: CCC(CC)C(c1nc2nc(Cl)ncc2c(=O)n1Cc1ccccc1)n1cc(CCN2C(=O)c3ccccc3C2=O)nc1-c1ccc(C)cc1
Agent: NN
Solvent: CCO
Product: CCC(CC)C(c1nc2nc(Cl)ncc2c(=O)n1Cc1ccccc1)n1cc(CCN)nc1-c1ccc(C)cc1
Temperature: 5 °C

Procedure:
Formula I where R1 is H; R3 is Cl; R5 is Benzyl; R6 is Isopentyl; R6′ is H; R7 taken together with R8 is 4-(2-Amino-ethyl)-2-p-tolyl-imidazol-1-yl-; W and Y are —C═; X and Z are —N═: A solution of 2-(2-{1-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-yl)-2-ethyl-butyl]-2-p-tolyl-1H-imidazol-4-yl}-ethyl)-isoindole-1,3-dione (290 mg, 0.423 mmol) and anhydrous hydrazine (98 mg, 3.06 mmol) in EtOH (12 mL) is refluxed for 3.0 h. The reaction is cooled to 5° C. and a precipitate is filtered off. The filtrate is concentrated in vacuo and purified by flash chromatography (silica gel, 90:9:1 methylene chloride:methanol:ammonium hydroxide as eluent) to provide the title compound, (±)-2-{1-[4-(2-amino-ethyl)-2-p-tolyl-imidazol-1-yl]-2-ethyl-butyl}-3-benzyl-7-chloro-3H-pyrimido[4,5-d]pyrimidin-4-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][CH2:44][CH2:45][OH:46]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:43][CH2:44][CH2:45][OH:46])=[O:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCCO)(CC1)CC2
Yield: 62.4 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-aminoethanol (6.9 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-2-hydroxyethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (27.2 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40](=[O:43])[CH2:41][CH3:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:37]1[CH2:38][CH2:39][N:34]([C:40](=[O:43])[CH2:41][CH3:42])[CH2:35][CH2:36]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 16 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-(piperazin-1-yl)propan-1-one as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[S:11])[NH2:10])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:24])[CH2:18][C:19](=O)[CH:20](Br)[CH3:21])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:24])[CH2:18][C:19]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[S:11][C:20]=1[CH3:21])[CH3:15]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)C(C)Br
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 47.2 %

Procedure:
To a solution of 4-trifluoromethyl-benzene-thioamide (1.845 g, 9 mmol) in ethanol (15 mL, 200 proof) add ethyl-4-bromo-3-oxo-pentanoate (2.07 g, 9 mmol). Seal this solution warm the solution to 170° C. in a Personal Chemistry™ microwave oven and stir at this temperature for 20 min. Cool the resulting solution to room temperature, concentrate under reduced pressure and purify the residue by flash chromatography (elute with 30% ethyl acetate/10% dichloromethane in heptane) and obtain the title compound as a white solid (1.4 g). MS (ESI) m/z 330 (M+H); H1 NMR (CDCl3) δ1.87 (bs, 1H), 2.49 (s, 3H), 4.86 (s, 2H), 7.67 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:10]([O:14][CH2:15][CH2:16][O:17][CH:18]=[CH2:19])[CH:11]1[O:13][CH2:12]1>>[CH2:10]([O:14][CH2:15][CH2:16][O:17][CH:18]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH:18]([O:17][CH2:16][CH2:15][O:14][CH2:10][CH:11]1[O:13][CH2:12]1)[CH3:19])=[O:8])[CH3:19])[CH:11]1[O:13][CH2:12]1
Reactant: O=C(O)CCCC(=O)O
Reactant: C=COCCOCC1CO1
Product: CC(OCCOCC1CO1)OC(=O)CCCC(=O)OC(C)OCCOCC1CO1
Reaction time: 2 h

Procedure:
Glutaric acid (1.32 g; 0.01 moles) was added slowly over about 20 minutes to a stirred reaction flask containing 2-vinyloxyethyl glycidyl ether (prepared as described by Sawamoto et. Al in J. Polym. Sci., Part A 1987, V. 25, 2717) at 80° C. After all the acid was added, heating and stirring was continued for a further 2 hours. On cooling, the product, bis-[α-(2-glycidoxyethoxy)ethyl]glutarate, was obtained in quantitative yield. The structure of the product was confirmed by 1H NMR and IR analysis. Previous synthesis of polyepoxides by addition of 2-vinyloxyethyl glycidyl ether to polycarboxylic acids has previously been reported to occur in the presence of acid catalysts by Tofimov et. al (Review Heteroatom Chem. 1993, V.9, 205). Such catalysts are undesirable as they tend to reduce the storage stability of the epoxide monomer and reduce the degradation temperature of the cured adhesive polymer.
Reaction SMILES: [S:1]([Cl:4])(Cl)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9](S(O)=O)=[CH:8][CH:7]=1>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:1]([Cl:4])=[O:2])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(O)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(Cl)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.53 mL) is added to an ice-cooled solution of 4-bromobenzenesulfinic acid (400 mg) in dichloromethane (15 mL) under an argon atmosphere. The reaction mixture is stirred for 2 h at 0° C., warmed to room temperature, and stirred for an additional 30 min. The mixture is concentrated and the residue is co-evaporated twice with toluene to give crude 4-bromobenzenesulfinic chloride, which is dissolved in tetrahydrofuran (3 mL) and cooled to −78° C. n-Butyllithium (1.6 M in hexane; 2.26 mL) is added to 2,2,2-trifluoroacetamide (205 mg) in tetrahydrofuran (3 mL) at −78° C. and the reaction mixture is stirred for 10 min. The mixture is added to the 4-bromobenzenesulfinic chloride solution at −78° C. and the reaction mixture is stirred for 1 h. The cooling bath is removed and the reaction is quenched by addition of water and brine. The aqueous layer is extracted with ethyl acetate and the combined extracts are washed with brine and concentrated in vacuo to give the title compound which is used for the next step without further purification. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=314 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:12]=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][CH2:12][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1nc2ccccc2cc1Br
Product: Brc1cc2ccccc2nc1CNCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 8, Step 2, using the following starting materials: 3-bromo-quinoline-2-carbaldehyde and benzylamine
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:57]=[CH:58][CH:59]=1)[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]([CH2:43][CH2:44][NH:45][C:46](=[O:56])[CH2:47][CH:48]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH3:49])[C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)=O)(C)(C)C>>[ClH:27].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:57]=[CH:58][CH:59]=1)[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]([CH2:43][CH2:44][NH:45][C:46](=[O:56])[CH2:47][CH:48]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH3:49])[C:29](=[O:42])[C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:34][CH:35]=1
Reactant: CC(CC(=O)NCCN(C(=O)c1ccc(-c2ccccc2)cc1)c1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(CC(=O)NCCN(C(=O)c1ccc(-c2ccccc2)cc1)c1ccc(Cl)cc1Oc1cccc(CN)c1)c1ccccc1
Yield: 189.9 %

Procedure:
A 2 N hydrochloric acid/ethyl acetate solution (4 ml) of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-[2-(3-phenylbutyryl)aminoethyl]-4-phenylbenzamide (0.1 g, 0.14 mmols) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The solid precipitated was taken out through filtration, and washed with ethyl ether to give an amorphous solid of N-[2-[3-(aminomethyl)phenoxy]-4-chlorophenyl]-N-[2-(3-phenylbutyryl)aminoethyl]-4-phenylbenzamide hydrochloride (0.087 g, 95%).
Reaction SMILES: [CH2:1]=[CH:2]C(=C)C.[CH3:6][O:7][C:8]([O:12][CH2:13][C:14]#[CH:15])([CH2:10][CH3:11])[CH3:9].BrCC>CCCCCC>[CH3:6][O:7][C:8]([CH3:9])([O:12][CH2:13][C:14]#[C:15][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: C#CCOC(C)(CC)OC
Reactant: C=CC(=C)C
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(CC)OC
Temperature: -38 °C
Reaction time: 0.42 h
Yield: 89.1 %

Procedure:
890 mg (127 mmol) of granulated lithium were added within 5 minutes to 100 ml (4.0 mol) of liquid ammonia at −40° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 5.94 g (86.6 mmol) of isoprene was added portion wise within 10 minutes, whereas the solution gets white at the end of the addition. The mixture was stirred for 25 minutes at −38° C. 9.1 g (69.5 mmol) of 2-methoxy-2-prop-2-ynyloxy-butane (97.4% GC) were added with a dropping funnel to the reaction mixture at −38° C. within 25 minutes. The reaction mixture was held at −38° C. for about 1 hour. 14 g (128.5 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1 hour and 30 minutes. 50 ml of water was added to the reaction mixture at 40° C., and the mixture was stirred until all salt was dissolved. The mixture is transferred into a separatory funnel and the layers were separated. The aqueous layer is extracted with 127 ml of n-hexane. The organic layers were dried over 0.5 g of anhydrous sodium sulphate and concentrated under reduced pressure (40° C., 60 mbar), and the crude product (1-(1-methoxy-1-methyl-propoxy)-pent-2-yne) was analyzed by GC. 10.54 g of crude 1-(1-methoxy-1-methyl-propoxy)-pent-2-yne were obtained with a purity of 87.1% (yield 77.6% based on 2-methoxy-2-prop-2-ynyloxy-butane).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:13])=[O:12])[C:3]1=[O:15].[Na:16].S1C2C=CC=CC=2N=C1S[O:27][C:28](=O)/[C:29](/[C:42]1[N:43]=[C:44]([NH2:47])[S:45][CH:46]=1)=[N:30]\[O:31][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[CH3:33]>CC(C)=O.O>[NH2:47][C:44]1[S:45][CH:46]=[C:42](/[C:29](=[N:30]/[O:31][C:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:34])[CH3:33])/[C:28]([NH:1][C@H:2]2[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:12])=[O:13])[C:3]2=[O:15])=[O:27])[N:43]=1.[Na:16]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)OSc1nc2ccccc2s1)c1csc(N)n1
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1

Procedure:
1.62 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidine-sulfonic acid-sodium salt in 180 ml of acetone-water (2:1) are stirred with 3.87 g of (Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetic acid 2-benzthiazolyl-thioester at room temperature for 15 hours. After removal of the acetone in vacuo and the addition of 50 ml of water, crystals are obtained which are washed with water. The mother liquor is evaporated under reduced pressure at 37° C. and chromatographed (MCI Gel, water as eluting agent). After lyophilization (3S,4S)-3-[(2-amino-4-thiazolyl)-2-(Z)-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulfonic acid-sodium salt is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)=[CH:8]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]2=[O:13])=[CH:33][CH:34]=1
Reactant: CN(C)CCN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
According to Scheme 19 Step 5: tert-Butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl(2-(dimethylamino)ethyl)carbamate (0.16 mmol, 79.0 mg) was dissolved in dry CH2Cl2 (30 mL). Then TFA (7 mL) was added dropwise and the resulting solution was stirred at room temperature for 3 hours. Then the solvent was evaporated under reduced pressure and the resulting residue thus obtained was resulting suspension was taken up in CH2Cl2, washed with a saturated aqueous NaHCO3 solution. The organic solvent was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2/MeOH(NH3)sat. 95/5. The product fractions were collected and the solvent was evaporated to yield 1-(4-chlorobenzyl)-5-(4-(2-(dimethylamino)ethylamino)phenyl)pyridin-2(1H)-one (16.4 mg, 26%)
Reaction SMILES: [Si:1]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][NH:15][C:13]=2[N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[CH:20]([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][N:15]([CH:20]([CH3:22])[CH3:21])[C:13]=2[N:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2cc[nH]c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Cl)nc(N[Si](C)(C)C(C)(C)C)nc21
Yield: 99.1 %

Procedure:
2-(t-Butyl-dimethylsilanyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CXXII) (5 g, 17.7 mmol), 2-iodopropane (4.5 g, 26.6 mmol) and K2CO3 (4.3 g, 26.6 mmol) in DMF (20 mL) were reacted at ambient temperature for 15 h. After addition of H2O (50 mL) to the reaction mixture, the aqueous solution was extracted with EtOAc (300 mL) and the organic layer was washed with a brine solution (50 mL) and dried with Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (pet ether/EtOAc=10/1 to 5/1) to afford 2-(t-butyl-dimethylsilyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXIII, 5.7 g, 100%) as a light yellow oil. LCMS: (ESI) m/z=325 (M+H)+.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.Cl>N1C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][CH:9]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A mixture of ethanesulfonyl chloride (2.1 mL, 22 mmol), and 4-bromoaniline (3.44 g, 20 mmol) in pyridine (35 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N HCl solution and extracted with ether. The combined organic layers were dried over magnesium sulfate, and concentrated. The solid was triturated with hexane to afford the title compound (4.85 g, 92%).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].Br[C:17]1[S:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:17]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:14][CH2:13]2)[S:18][CH:19]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Product: CC(C)c1noc(N2CCC(Oc3nc(Br)cs3)CC2)n1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42, using 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol and 2,4-dibromothiazole
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([CH3:16])=[CH:4][N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(Cl)Cl.CO>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH3:16])=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2nc(Cl)ncc2C)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(-c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2C)c1
Yield: 20 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-methoxyphenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 20% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.59 (d, 2H, J=8.2 Hz), 7.37 (t, 1H, J=8.0 Hz), 7.24 (d, 2H, J: not calculated due to overlapping peaks), 7.16 (m, 2H), 6.98 (d, 1H, J=8.2 Hz), 3.85 (s, 3H), 3.49 (s, 2H), 2.57 (bs, 8H), 2.36 (s, 3H), 2.24 (s, 3H); MS (ESI): 404.4 [M+H]+, 202.9 [M+2H]2+.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([O:28]CC)=[O:27])[CH2:22][CH2:21]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Li+].S(=O)(=O)(O)O>O>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
70 mg (0.17 mmol) of ethyl trans-4-(4,5-diphenylpyrimidin-2-ylamino)-cyclohexanecarboxylate were mixed with 872 μl of tetrahydrofuran and 872 μl of 1N aqueous lithium hydroxide solution and stirred at room temperature for 48 hours. The reaction mixture was diluted with water and acidified with sulfuric acid, and the resulting precipitate was filtered off with suction. 64 mg (98%) of the desired product were obtained.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:15]([Cl:19])[C:16]=2[Cl:18])[CH2:11][C:10]1([CH3:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>S(=O)(=O)(O)O.C(O)(=O)C>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:15]([Cl:19])[C:16]=2[Cl:18])[CH2:11][C:10]1([C:25]1[CH:30]=[CH:29][C:28]([CH2:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6])=[CH:27][CH:26]=1)[CH3:31]
Reactant: O=C(CCl)NCO
Reactant: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1(c2ccc(CNC(=O)CCl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
Well-pulverized N-hydroxymethyl-2-chloroacetamide (3.37 g., 0.0274 mole) is added portionwise to (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (10.0 g., 0.0274 mole) in 36 N sulfuric acid (100 ml.) and acetic acid (100 ml.) with stirring at 40°-50° C. over one-half hour. Additional N-hydroxymethyl-2-chloroacetamide (1.68 g., 0.014 mole) is added over a four hour period until no starting material remains. After stirring at 25° C. for 16 hours the reaction mixture is added to crushed ice-water (2 l.) to precipitate 11.9 g. of {1-oxo-2-[4-(2-chloroacetamidomethyl)phenyl]-2-methyl-6,7-dichloro-5-indanyloxy}-acetic acid which melts at 138°-141° C. and is used in the next step without purification.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[C:17]([OH:19])=O.Cl>C(OCC)C>[C:17]([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:15][C:16]=2[C:4]=1[CH3:3])(=[O:19])[CH3:1]
Reactant: [Li]C
Reactant: Cc1c(C(=O)O)ccc2c1[nH]c1ccccc12
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1ccc2c([nH]c3ccccc32)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
15 ml of a 1.5M solution of methyllithium (22 mmol) in diethyl ether was added to 30 ml of a solution of 1.25 g of 1-methylcarbazol-2-ylcarboxylic acid (5.5 mmol--as obtained in Example 26) in diethyl ether, at a temperature of -78° C. The reaction mixture was then warmed to room temperature and stirred for 1 hour. After this time, the mixture was poured into a 0.5N aqueous solution of hydrogenchloride. The aqueous layer was extracted with ethyl acetate and the resulting organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 25% v/v solution of ethyl acetate in hexane) to yield 1.08 g (88%) of the title compound as an amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[CH:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH:11]=[CH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccncc1)c1ccc([N+](=O)[O-])cc1

Procedure:
41.25 G. of 4'-nitroacetophenone are suspended in 500 ml. of water and heated at 70° C. with stirring. Then, 24 ml. of isonicotinaldehyde are added and the reaction mixture is treated three times at intervals of 30 minutes with 5 ml. each time of a 6% NaOH solution in water/methanol (2:1). Subsequently the reaction mixture is left to react at 70° C. for 8 hours. The crystals which form are filtered off, boiled up twice with 500 ml. of ethanol each time and subsequently washed with ether to yield 4'-nitro-3-(4-pyridyl)-acrylphenone with a melting point of 218°-221° C.