Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][N:3]12.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C[O-].[Na+].Cl>CO>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[C:15]1[C:4]2=[N:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[CH:10][C:11]=3[C:2](=[O:1])[N:3]2[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc2nc3n(c(=O)c2c1)CCC3
Reactant: Cc1ccccc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1C=C1CCn2c1nc1ccc(C(=O)O)cc1c2=O
Reaction time: 48 h
Yield: 59.4 %

Procedure:
1,2,3,9-tetrahydro-9-oxo-pyrrolo[2,1-b]quinazoline-7-carboxylic acid (1.4 g) was reacted with 2-methyl-benzaldehyde (1.65 g) in methanol (50 ml) in the presence of sodium methoxide (1.3 g) under stirring at the reflux temperature for 48 hours. After cooling the reaction mixture was acidified with 37% HCl and the precipitate was filtered and washed with water until neutral: crystallization from chloroform-ethanol gave 1.2 g of 3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-pyrrolo[2,1-b]quinazoline-7-carboxylic acid, m.p. 285°-287° C., NMR (CF3COOD) δp.p.m.: 2.58 (s) (3H, CH3), 3.66 (m) (2H, C-2 protons), 4.74 (t) (2H, C-1 protons), 7.40-7.85 (m) (4H, phenyl protons), 8.09 (d) (1H, C-5 proton), 8.65 (t) (1H, =CH--), 8.84 (d d) (1H, C-6 proton), 9.30 (d) (1H, C-8 proton).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=[O:13])[CH3:12].C[O:15][C:16]1C=CC=C[C:17]=1C1CC(=O)CC(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16](=[O:15])[CH2:12][C:11](=[O:13])[CH2:10]1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)C=Cc1ccc(F)cc1Br
Product: O=C1CC(=O)CC(c2ccc(F)cc2Br)C1

Procedure:
The title compound was prepared from 4-(2-bromo-4-fluoro-phenyl)-but-3-en-2-one (34 g, 142 mmol), stage 1, following the procedure describing the synthesis of 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (example 1/a stage 2).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH3:15])[CH2:9]2)[N:5]=[C:4]([NH:16][CH3:17])[N:3]=1.[F:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C@H:10]1[O:11][CH2:12][C@@H:13]([CH3:14])[N:8]([C:6]2[N:5]=[C:4]([NH:16][CH3:17])[N:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([F:18])[CH:26]=3)[CH:7]=2)[CH2:9]1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C)OC[C@H]2C)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C)OC[C@H]2C)n1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a solution of 4-chloro-6-[(2R,5R)-2,5-dimethyl-4-morpholinyl]-N-methyl-2-pyrimidinamine (430 mg, 1.675 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (621 mg, 2.51 mmol) in 1,4-dioxane (2 mL) and water (1.00 mL) in a microwave reaction vessel stirred under nitrogen at room temperature was added Na2CO3 (355 mg, 3.35 mmol) and Pd(Ph3P)4 (194 mg, 0.167 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1 hour. After cooling the reaction to room temperature, the mixture was filtered through a pad of celite, and the filter cake was washed with THF (3×30 mL) and CH3OH (3×30 mL). The filtrate was purified with a silica gel (300-400) column and was eluted with Hex/EtOAc (2:1 to 1:2) to afford the title compound (315 mg) as a light yellow solid. LC-MS (ES) m/z=342 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH2:14][CH2:13][S:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:17](=[O:18])[C:16]([Cl:21])([Cl:20])[Cl:15])[N:9]2[CH2:14][CH2:13][S:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccn2c1CSCC2
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1CSCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]thiazine-8-carboxylic acid ethyl ester (Comp. No. 2c) (0.5 g, 2.37 mmol) in anhydrous dichloromethane (1.7 ml) was added trichloro-acetyl chloride (1.08 g, 5.9 mmol). The resulting mixture was stirred overnight at room temperature, after which a second portion of trichloro-acetyl chloride (0.43 g, 2.37 mmol) was added. The resulting mixture was stirred for 4 h, and then evaporated to dryness. The crude product was purified by silica gel chromatography (eluting with 5 to 50% ethyl acetate in heptane) to give 0.592 g of 6-(2,2,2-Trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]thiazine-8-carboxylic acid ethyl ester. LC/MS (method 4): Rt=1.41 min; m/z=356.09 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][N:8]=[C:7]([CH3:13])[N:6]=1>>[CH2:11]([C:10]1[C:5]([NH:2][NH2:3])=[N:6][C:7]([CH3:13])=[N:8][CH:9]=1)[CH3:12]
Reactant: NN
Reactant: CCc1cnc(C)nc1Cl
Solvent: O
Product: CCc1cnc(C)nc1NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
Hydrazine monohydrate (0.398 mL, 5.24 mmol) was added to 4-chloro-5-ethyl-2-methylpyrimidine (216 mg, 1.31 mmol). The reaction mixture was stirred in a sealed tube at room temperature overnight. Remaining hydrazine was evaporated. Purification by column chromatography (SiO2, methanol/ammonia/dichloromethane) to afforded the desired product (136 mg, 68.2%) as an amorphous off-white solid. MS: m/z=153.11 (M+H+)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:34]([CH3:48])[CH2:35][CH2:36][N:37]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:37][CH2:36][CH2:35][CH:34]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[C:31]#[N:32])[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[CH3:48]
Reactant: CS(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(S(C)=O)cc2)CC1

Procedure:
Using general procedure C with 4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.57 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (270 mg, 1.2 mmol) followed by general procedure D afforded 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methanesulfinyl-phenyl)-amino]-methyl}-benzonitrile as a white solid (133 mg, 55% over 3 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:11][C:10]([O:12]C)=[CH:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[OH-].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: COC1=CC(C#N)(c2ccc(Cl)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CC(=O)C1
Reaction time: 10 h
Yield: 89.8 %

Procedure:
1-(4-Chloro-phenyl)-3-methoxy-cyclobut-2-enecarbonitrile (8.80 g, 40.1 mmol), 4-toluene sulfonic acid (2.30 g, 12.1 mmol), and 2 N HCl were dissolved in acetone/water 100:10 (110 ml) and stirred for 10 h under reflux. The reaction mixture was alkalized with aqueous NaOH and extracted with ethyl acetate. The combined organic layers were washed with water and subsequently with saturated sodium chloride solution and dried with sodium sulphate. The product was obtained as an orange oil (7.40 g, 36.0 mmol) that was sufficiently pure for the next step.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([N:14]([CH:22]([CH3:24])[CH3:23])[CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][OH:21])([CH3:13])[CH3:12].O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:22]([N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH:20]=[O:21])([CH3:24])[CH3:23]
Reactant: CC(C)N(CC#CCCCO)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)N(CC#CCCC=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of dimethyl sulfoxide (25.1 ml, 353 mmol) in CH2Cl2 (75 ml) was added to a stirred solution of oxalyl chloride (14.75 ml, 169 mmol) in CH2Cl2 (370 ml) at -60° C. The reaction mixture was stirred for 1 hour and a propylamino-solution of 6-diisopropylaminohex-4-yn-1-ol (29.07 g, 147.5 mmol) in CH2Cl2 (150 ml) was added and the reaction mixture was stirred for 90 minutes and then allowed to warm to room temperature. Water (200 ml) was then added and the aqueous layer was reextracted with chloroform (3 times 100 ml). The organic layers were combined, washed with brine and dried (MgSO4). Evaporation of the solvent yielded crude product, which was distilled to give 12.96 g of the aldehyde: bp 90-5 (0.25 mm Hg); 1H NMR (CDCl3) δ1.05(d, 12H), 2.00- 2.67(m, 4H), 2.83-3.50(m, 4H), 9.67(s, 1H).
Reaction SMILES: Br[C:2]1(Br)[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>CS(C)=O>[C:18]1([NH:24][N:25]=[C:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH2:3]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1CCC(Br)(Br)c2ncc(C(=O)O)c(=O)n21
Reactant: NNc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: CS(C)=O
Product: CC1CCC(=NNc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Reaction time: 72 h
Yield: 64 %

Procedure:
0.73 g. (0.002 moles) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 2 ml. of dimethyl sulfoxide. To the solution 0.2 ml. (0.002 moles) of phenyl hydrazine and 0.5 ml. (0.004 moles) of N,N-dimethylaniline are added. Thereafter the reaction mixture is allowed to stand for three days. The precipitated crystals are filtered off and washed with methanol. The product is purified by alkaline/acidic precipitation. 0.4 g. (64.0%) of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are obtained, melting at 254° to 255° C.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2([OH:21])[CH2:19][CH2:18][O:17][CH:16]2[CH3:20])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34]C(N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[OH:21][C:15]1([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:34]=[CH:35][C:30]([N:26]5[CH2:27][CH2:28][CH2:29][N:23]([CH3:22])[CH2:24][CH2:25]5)=[CH:31][CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:19][CH2:18][O:17][CH:16]1[CH3:20]
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C2(O)CCOC2C)cc1N=CN(C)C
Product: CC1OCCC1(O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(3-hydroxy-2-methyltetrahydrofuran-3-yl)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 440.57 (C23H28N4O3S) was obtained in this way; MS (ESI): 441 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=3[N:19]=[CH:18]2)=[CH:13][CH:12]=1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.Cl.CN.CCN(C(C)C)C(C)C>C1COCC1>[CH3:29][NH:31][C:26]([C:24]1[CH:23]=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:16][CH:15]=3)[CH:18]=[N:19][C:20]=2[CH:25]=1)=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1-{4-[2-(Pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid (100 mg, 0.266 mmol) and 1,1′-carbonyldiimidazole (86 mg, 0.53 mmol) were dissolved in dry THF (2 mL) under a N2 atmosphere. The reaction mixture was heated at 60° C. for 1 h and then cooled to rt. Methylamine hydrochloride (27 mg, 0.40 mmol) and N,N′-diisopropylethylamine (52 mg, 0.40 mmol, 70 μL) were added and the reaction was allowed to stir at rt. After 18 h, the reaction mixture was concentrated in vacuo, diluted with CH2Cl2 (2 mL), and washed with distilled water (1 mL). The aqueous phase was back extracted with CH2Cl2 (2 mL×5) and the combined organic extracts were concentrated in vacuo. The resulting yellow solid was purified using the Waters mass-directed HPLC purification system to give N-methyl-1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxamide as a white powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.57 (s, 1H), 8.49 (brq, J=4.4 Hz, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.19 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.85 (dd, J=8.6, 1.4 Hz, 1H), 7.74 (ddd, J=8.8, 6.8, 2.0 Hz, 1H), 7.61 (ddd, J=5.2, 3.2, 3.2 Hz, 2H), 7.55 (d, J=9.2 Hz, 1H), 7.23 (ddd, J=5.8, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J=7.2, 5.2, 1.2 Hz, 1H), 6.88 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.63 (m, 2H), 4.43 (m, 2H), 2.82 (d, J=4.8 Hz, 3H). MS(ES+): m/z 389 [MH+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:11]([CH2:21][CH2:22][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[OH:24])[C:10]2=[O:32])=[CH:5][CH:4]=1.[C:33]([OH:47])(=[O:46])[CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][C:43](O)=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(N(CC)CC)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:23]([OH:24])[CH2:22][CH2:21][CH:11]2[C:10](=[O:32])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:43]([CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][C:33]([OH:47])=[O:46])=[O:44])=[CH:4][CH:5]=3)[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)COCCOCCOCC(=O)O
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CNC(=O)COCCOCCOCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 64 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5), and 21 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 327 mg of 3,6,9-trioxaundecanedioic acid, 57 μl of diisopropylcarbodiimide, 50 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20->10/90). This gave the product of molecular weight 638.70 (C34H39F1N2O9); MS (ESI) 639.27 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)cs2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[NH:11][C:12]4[N:13]([N:17]=[C:18]([C:20]([O:22]C)=O)[N:19]=4)[C:14](=[O:16])[CH:15]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[NH3:24]>>[NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[NH:11][C:12]4[N:13]([N:17]=[C:18]([C:20]([NH2:24])=[O:22])[N:19]=4)[C:14](=[O:16])[CH:15]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Reactant: N
Product: NC(=O)c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Yield: 45 %

Procedure:
Methyl 5-(1H-benzo[d][1,2,3]triazol-6-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxylate (80 mg, 1.0 eq) in methanolic ammonia (8 ml) was stirred overnight at 80° C. Then the pH value of the solution was adjusted to pH 4 with HCL (3N). The solids were collected by filtration, washed with water (10 ml) and purified by prep-HPLC to afford 5-(1H-benzo[d][1,2,3]triazol-6-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxamide as a white solid (34.8 mg, 45%).
Reaction SMILES: [CH2:1]1[C@H:5](N2C(=O)NC(=O)C=C2)[O:4][C@H:3]([CH2:14][OH:15])[C@H:2]1[OH:16].[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([NH:22][CH:23]=[N:24]2)=[C:20]([NH2:27])[N:19]=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>>[CH:23]1[N:24]([C@@H:5]2[O:4][C@H:3]([CH2:14][OH:15])[C@@H:2]([OH:16])[CH2:1]2)[C:25]2[C:21](=[C:20]([NH2:27])[N:19]=[C:18]([Cl:17])[N:26]=2)[N:22]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
reaction of 2-deoxyuridine with 2-chloroadenine, in the presence of uridine phosphorylase (UPase) and purine nucleoside phosphorylase (PNPase) in an aqueous reaction medium possibly containing up to 40% v/v of an aprotic dipolar solvent, to obtain cladribine dissolved in said reaction medium; b) isolation of the cladribine by precipitation by means of concentration and alkalinisation of the reaction medium up to a pH of 11.5-12.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[C:14]3[CH:25]=[C:24]([OH:26])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:15]=3[O:16][CH:17]=2)=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+]([O-])(O)=[O:28].O.C(Cl)(Cl)Cl.CO>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:11]([C:13]1[C:14]2[C:25](=[O:28])[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]=2[O:16][CH:17]=1)=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)c2coc3c2cc(O)c2ccccc23)cc1OC
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)c2ccccc2-3)cc1OC
Temperature: 45 °C

Procedure:
To a suspension of compound 24 (100 mg, 0.28 mmol) in glacial acetic acid (1.5 mL) at room temperature was added nitric acid (0.2 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 45° C. for 30 min, allowed to cool to room temperature, and poured into cold water. The resulting precipitate was filtered and recrystallized to afford compound SKC-NF-02 (45 mg, 43%) as an orange solid. TLC Rf=0.4 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 8.13 (d, J=7.0 Hz, 1H), 7.81 (m, 2H), 7.74 (app t, 1H), 7.61 (app s, 1H), 7.55 (app t, 1H), 7.43 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 3.96 (s, 6H); MS (ES) m/z 363 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1
Reactant: CN(C)[C@H]1CC[C@H](CN)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NC[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (300 mg, 1.2 mmol) was reacted with trans-4-(aminomethyl)-N,N-dimethylcyclohexanamine (350 mg, 1.5 mmol) to afford the desired product (400 mg, 86%) as an orange-red solid: 1H NMR (300 MHz, CD3OD) δ 8.95 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 4.07 (d, J=6.5 Hz, 2H), 2.69 (s, 3H), 2.32 (s, 6H), 2.13-1.95 (m, 4H), 1.43-1.08 (m, 4H); ESI MS m/z 361 [M+H]+
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH:8]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].Cl>CN(C=O)C.O>[CH:14]1([CH:8]([C:25]2[CH:24]=[CH:23][C:22]([N+:27]([O-:29])=[O:28])=[C:21]([F:20])[CH:26]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(Cl)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
8.2 g of potassium tert-butylate were dissolved in 70 mL of DMF and cooled to −45° C. To this, a mixture of ethyl 2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and 1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 mL) was gently added dropwise and stirring was continued for a further 20 minutes. The reaction mixture was set to pH 4 with 16% strength aq. HCl, diluted with 25 mL of water, and extracted with EA (3×50 mL). After combining the organic phases, they were washed with water and sat. aq. NaCl solution, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EA in cyclohexane) and yielded 5.5 g (49%) of the desired product.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Br:24][CH2:25][CH2:26][OH:27]>CCOCC.O>[Si:1]([O:27][CH2:26][CH2:25][Br:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 101.1 %

Procedure:
A mixture of tert-butyldiphenylsilyl chloride (20.32 g, 74.03 mmol) and imidazole (6.25 g, 91.9 mmol) was treated dropwise with 2-bromoethanol (47, 5 mL, 8.87 g, 70.8 mmol). Stirring was continued for 12 h. The mixture was diluted with Et2O and water. The phases were separated, and the aqueous layer was extracted Et2O. The organic extract was washed with water and dried over Na2SO4. Concentration of the sample yielded a pale brown oil (26.01 g, 97%): 1H NMR δ 1.11 (s, 9H), 3.45 (t, J=6.3 Hz, 2H), 3.96 (t, J=6.3 Hz, 2H), 7.42-7.47 (m, 6H), 7.70-7.73 (m, 4H); 13C NMR δ 19.52, 27.03, 33.43, 64.24, 128.04, 130.10, 133.49, 135.84.